Disease Information

General Information of the Disease (ID: DIS00046)

• Name: Brain cancer
• ICD: ICD-11: 2A00

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  DISM: Drug Inactivation by Structure Modification

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 40 drug(s) in total

Alectinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [1]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L
• Resistant Drug: Alectinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NBLW cells; Brain; Homo sapiens (Human); CVCL_VJ90
• In Vitro Model: NBLW-R cells; Brain; Homo sapiens (Human); CVCL_VJ91
• Experiment for Molecule Alteration: Sangersequencing assay; Targeted deep sequencing assay
• Experiment for Drug Resistance: Array CGH assay
• Mechanism Description: Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.

Anagrelide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [2]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Anagrelide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: MDCK cells; Kidney; Canis lupus familiaris (Dog) (Canis familiaris); CVCL_0422
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Azacitidine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [3]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: Azacitidine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• In Vivo Model: Female athymic nude mouse (NCI-Frederick) model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Tumor volume measurement assay

Bevacizumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132S (c.394C>A)
• Sensitive Drug: Bevacizumab
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.R132S (c.394C>A) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: Bevacizumab
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [4]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132L (c.395G>T)
• Sensitive Drug: Bevacizumab
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.R132L (c.395G>T) in gene IDH1 cause the sensitivity of Bevacizumab by aberration of the drug's therapeutic target

Brigatinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ALK tyrosine kinase receptor (ALK) [5]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174V (c.3520T>G)
• Sensitive Drug: Brigatinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: PC12 cells; Adrenal gland; Rattus norvegicus (Rat); CVCL_0481
• In Vitro Model: CLB-PE cells; Brain; Homo sapiens (Human); CVCL_9534
• In Vitro Model: CLB-GE cells; Bone marrow; Homo sapiens (Human); CVCL_9530
• In Vitro Model: CLB-BAR cells; Brain; Homo sapiens (Human); CVCL_9519
• In Vivo Model: Female Balbc/nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Resazurin disc test assay
• Mechanism Description: Anaplastic lymphoma kinase (ALK) is a tyrosine kinase receptor which has been implicated in numerous solid and hematologic cancers. Brigatinib is an effective inhibitor of ALK kinase activity in ALK addicted neuroblastoma

Carmustine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: GSTP1 is the first major mechanism of resistance alkylator agents encounter after entering the cancer cell cytoplasm. GSTP1 acts to enzymatically conjugate glutathione to the reactive metabolites of BCNU. The mechanisms by which GSTP1 may be up-regulated in gliomas are under investigation. Constitutive expression is thought to be influenced by the proximal promoter factor Sp1, whereas increased expression levels may result from stabilization of GSTP1 mRNA. GSTP1 expression has been reported to be induced by drug exposure, indicating that it may play a role in acquired drug resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [7]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SWOZ2 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SWOZ2-BCNU cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression.

Key Molecule: hsa-mir-221 [8]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3-k/PTEN/AKT signaling axis; Activation; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-221 regulated cell proliferation and BCNU resistance in glioma cells. Overexpression of miR-221 led to cell survival and BCNU resistance and reduced cell apoptosis induced by BCNU, whereas knockdown of miR-221 inhibited cell proliferation and prompted BCNU sensitivity and cell apoptosis. Further investigation revealed that miR-221 down-regulated PTEN and activated Akt, which resulted in cell survival and BCNU resistance. Overexpression of PTEN lacking 3'UTR or PI3-k/Akt specific inhibitor wortmannin attenuated miR-221-mediated BCNU resistance and prompted cell apoptosis. We propose that miR-221 regulated cell proliferation and BCNU resistance in glioma cells by targeting PI3-k/PTEN/Akt signaling axis.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein sprouty homolog 2 (SPRY2) [7]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Carmustine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SWOZ2 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: SWOZ2-BCNU cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR21 enhanced glioma cells resistance to carmustine via decreasing Spry2 expression.

Key Molecule: Phosphatase and tensin homolog (PTEN) [8]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Carmustine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: PI3K/PTEN/AKT signaling axis; Activation; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-221 regulated cell proliferation and BCNU resistance in glioma cells. Overexpression of miR-221 led to cell survival and BCNU resistance and reduced cell apoptosis induced by BCNU, whereas knockdown of miR-221 inhibited cell proliferation and prompted BCNU sensitivity and cell apoptosis. Further investigation revealed that miR-221 down-regulated PTEN and activated Akt, which resulted in cell survival and BCNU resistance. Overexpression of PTEN lacking 3'UTR or PI3-k/Akt specific inhibitor wortmannin attenuated miR-221-mediated BCNU resistance and prompted cell apoptosis. We propose that miR-221 regulated cell proliferation and BCNU resistance in glioma cells by targeting PI3-k/PTEN/Akt signaling axis.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Carmustine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: For drugs that have evaded cytosolic mechanisms of drug resistance, the nucleus is equipped with the capacity to remove BCNU or temozolomide alkyl groups from the O6-position of guanine via a reaction catalyzed by MGMT. Repair occurs before cross-link formation and involves an irreversible stoichiometric covalent transfer of the O6-alkyl DNA adduct to a cysteine within the active site of MGMT, resulting in the inactivation and subsequent depletion of enzyme activity. MGMT-mediated repair is rapid, with a half-life of 35 hours. MGMT enzyme recovery occurs via de novo synthesis. In malignant glioma patients, MGMT overexpression has been associated with resistance to BCNU and similar alkylating agents and was an independent predictor of poor survival. MGMT is also thought to contribute to temozolomide resistance, which we did not detect in our study. This may be related to the in vitro pharmacokinetic differences between BCNU and temozolomide.

Celecoxib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Prostaglandin G/H synthase 2 (PTGS2) [9]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Celecoxib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: MDA-175 cells; Pleural effusion; Homo sapiens (Human); CVCL_1400
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• Experiment for Molecule Alteration: Western blot analysis; Fluorescence microscopy assay
• Experiment for Drug Resistance: MTS assay; Crystal violet staining assay; Fluorescence-activated cell sorting (FACS) assay; Flow cytometry
• Mechanism Description: Celecoxib reverses the glioblastoma chemo-resistance to temozolomide through mitochondrial metabolism.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-204 [10]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Knockdown of LncRNA HOXD-AS1 suppresses proliferation, migration and invasion and enhances cisplatin sensitivity of glioma cells by sponging miR-20.

Key Molecule: HOXD antisense growth-associated long non-coding RNA (HAGLR) [10]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: Knockdown of LncRNA HOXD-AS1 suppresses proliferation, migration and invasion and enhances cisplatin sensitivity of glioma cells by sponging miR-20.

Key Molecule: hsa-miR-214-3p [11]

• Resistant Disease: Pediatric intracranial nongerminomatous malignant germ cell tumors [ICD-11: 2A00.07]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT Assay
• Mechanism Description: miR214-3p overexpression enhanced cisplatin resistance by downregulating the expression of its target, the apoptotic protein BCL2-like 11 (BCL2L11/BIM).

Key Molecule: hsa-mir-520f [12]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both Sk-N-AsCis24 and in parental Sk-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in Sk-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in postchemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting.

Key Molecule: hsa-let-7f-1 [13]

• Resistant Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: D425 cells; Brain; Homo sapiens (Human); CVCL_1275
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: High-Mobility Group Box 1 (HMGB1) is a direct target of miR-let-7f-1. HMGB1 is a highly conserved nuclear protein that functions as a chromatin-binding factor that bends DNA and promotes access to transcriptional protein assemblies on specific DNA targets. Overexpression of HMGB1 in cells treated with pSP and cisplatin blocked SPARC-induced cisplatin resistance indicating that overexpression of miR-let-7f-1 and a reduction in HMGB1 protein levels result in cellular resistance to cisplatin in SPARC over expressed cells. Earlier studies demonstrated that HMGB1 functions as a regulator of the balance between autophagy and apoptosis.

Key Molecule: hsa-let-7b [14]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell cycle; Inhibition; hsa04110
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression, resulting in resistance to cisplatin.

Key Molecule: hsa-mir-21 [15]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: BE(2) -M17 cells; Brain; Homo sapiens (Human); CVCL_0167
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Increased miR-21 expression might suppress the PTEN expression and eventually induce chemoresistance to cisplatin and increase cell proliferation.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: Cisplatin and etoposide are both substrates for membrane-bound efflux pumps, such as MRP and MDR1, which prevent their entry into the extracellular space of the central nervous system. The low levels of in vitro drug resistance noted for cisplatin and etoposide may be explained in part by the absence of such a barrier in our in vitro assay system.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [11]

• Resistant Disease: Pediatric intracranial nongerminomatous malignant germ cell tumors [ICD-11: 2A00.07]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Immunoblotting assay; Immunohistochemistry
• Experiment for Drug Resistance: MTT Assay
• Mechanism Description: miR214-3p overexpression enhanced cisplatin resistance by downregulating the expression of its target, the apoptotic protein BCL2-like 11 (BCL2L11/BIM).

Key Molecule: Baculoviral IAP repeat-containing protein 1 (BIRC1) [12]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: Significant overexpression of NAIP mRNA and protein was documented, while experimental modulation of NAIP levels in both Sk-N-AsCis24 and in parental Sk-N-AS cells confirmed that NAIP was responsible for the drug resistant phenotype by apoptosis inhibition. Furthermore, a decrease in the NAIP targeting microRNA, miR-520f, was also demonstrated to be partially responsible for increased NAIP levels in Sk-N-AsCis24. Interestingly, miR-520f levels were determined to be significantly lower in postchemotherapy treatment tumours relative to matched prechemotherapy samples, consistent with a role for this miRNA in the acquisition of drug resistance in vivo, potentially through decreased NAIP targeting.

Key Molecule: High mobility group protein B1 (HMGB1) [13]

• Resistant Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: D425 cells; Brain; Homo sapiens (Human); CVCL_1275
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; TUNEL assay
• Mechanism Description: High-Mobility Group Box 1 (HMGB1) is a direct target of miR-let-7f-1. HMGB1 is a highly conserved nuclear protein that functions as a chromatin-binding factor that bends DNA and promotes access to transcriptional protein assemblies on specific DNA targets. Overexpression of HMGB1 in cells treated with pSP and cisplatin blocked SPARC-induced cisplatin resistance indicating that overexpression of miR-let-7f-1 and a reduction in HMGB1 protein levels result in cellular resistance to cisplatin in SPARC over expressed cells. Earlier studies demonstrated that HMGB1 functions as a regulator of the balance between autophagy and apoptosis.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [14]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Cisplatin treatment leads to Let-7b suppression, which in turn up-regulates cyclin D1 expression, resulting in resistance to cisplatin.

Key Molecule: Phosphatase and tensin homolog (PTEN) [15]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: BE(2) -M17 cells; Brain; Homo sapiens (Human); CVCL_0167
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Increased miR-21 expression might suppress the PTEN expression and eventually induce chemoresistance to cisplatin and increase cell proliferation.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-204 [10]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assays
• Mechanism Description: miR-204 overexpression suppressed proliferation, migration and invasion and enhanced the DDP sensitivity in glioma cells.

Key Molecule: Maternally expressed 3 (MEG3) [16]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long non coding RNA MEG3 contributes to cisplatin induced apoptosis via inhibition of autophagy in human glioma cells.

Key Molecule: Long non-protein coding RNA (AC023115.3) [17]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR26a/GSk3Beta/Mcl1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC staining assay; Flow cytometry assay
• Mechanism Description: AC023115.3 sensitized glioma cell to cisplatin-induced apoptosis through regulation of the miR26a-GSk3beta-Mcl1 signalling. AC023115.3 acted as a miR26a sponge and inhibited its activity, thus increased the expression of GSk3beta.

Key Molecule: hsa-mir-26a [17]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: miR26a/GSk3Beta/Mcl1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC staining assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA AC023115.3 suppresses chemoresistance of glioblastoma by reducing autophagy. AC023115.3 acts as a competing endogenous RNA for miR26a and attenuates the inhibitory effect of miR26a on GSk3beta, leading to an increase in GSk3beta and a decrease in autophagy.

Key Molecule: hsa-mir-186 [18]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 186 reverses cisplatin resistance and inhibits the formation of the GIC phenotype by degrading YY1 in glioblastoma.

Key Molecule: hsa-miR-501-3p [19]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-501-3p sensitizes glioma cells to cisplatin via reducing protein levels of MYCN.

Key Molecule: hsa-mir-141 [20]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the IMR-32 and SH-SY5Y cells, lentivirus-induced miR-141 upregulation inhibited cancer proliferation, cell cycle progression, migration and increased cisplatin chemosensitivity in vitro. In addition, miR-141 upregulation reduced the in vivo growth of IMR-32 tumor explants. FUS was found to be inversely regulated by miR-141 in NB. Small interfering RNA (siRNA)-induced FUS downregulation had similar tumor-suppressive effects as miR-141 upregulation on NB cell proliferation, cell cycle progression, migration and cisplatin chemosensitivity.

Key Molecule: hsa-mir-873 [21]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bcl-2 was a direct target of miR 873, and miR 873 decreased the level of the Bcl-2 protein in cisplatin-resistant glioma cells. Notably, re-expression of Bcl-2 attenuated the function of miR 873 in cisplatin-resistant glioma cells and the sensitivity of the cells to cisplatin.

Key Molecule: hsa-mir-30d [22]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: hsa-mir-204 [23]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: hsa-mir-34 [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [17]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: miR26a/GSk3Beta/Mcl1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Dual luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC staining assay; Flow cytometry assay
• Mechanism Description: Long non-coding RNA AC023115.3 suppresses chemoresistance of glioblastoma by reducing autophagy. AC023115.3 acts as a competing endogenous RNA for miR26a and attenuates the inhibitory effect of miR26a on GSk3beta, leading to an increase in GSk3beta and a decrease in autophagy.

Key Molecule: Transcriptional repressor protein YY1 (TYY1) [18]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR 186 reverses cisplatin resistance and inhibits the formation of the GIC phenotype by degrading YY1 in glioblastoma.

Key Molecule: N-myc proto-oncogene protein (MYCN) [19]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-501-3p sensitizes glioma cells to cisplatin via reducing protein levels of MYCN.

Key Molecule: RNA-binding protein FUS (FUS) [20]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: In the IMR-32 and SH-SY5Y cells, lentivirus-induced miR-141 upregulation inhibited cancer proliferation, cell cycle progression, migration and increased cisplatin chemosensitivity in vitro. In addition, miR-141 upregulation reduced the in vivo growth of IMR-32 tumor explants. FUS was found to be inversely regulated by miR-141 in NB. Small interfering RNA (siRNA)-induced FUS downregulation had similar tumor-suppressive effects as miR-141 upregulation on NB cell proliferation, cell cycle progression, migration and cisplatin chemosensitivity.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [21]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bcl-2 was a direct target of miR 873, and miR 873 decreased the level of the Bcl-2 protein in cisplatin-resistant glioma cells. Notably, re-expression of Bcl-2 attenuated the function of miR 873 in cisplatin-resistant glioma cells and the sensitivity of the cells to cisplatin.

Key Molecule: Beclin-1 (BECN1) [22]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The effect of miR-30d on cisplatin sensitivity is mediated through the beclin 1-regulated autophagy.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [23]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: BDNF/NT-3 growth factors receptor (NTRK2) [23]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: Melanoma-associated antigen 12 (MAGEA12) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 2 (MAGEA2) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 3 (MAGEA3) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 6 (MAGEA6) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Crizotinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [1]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L
• Resistant Drug: Crizotinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NBLW cells; Brain; Homo sapiens (Human); CVCL_VJ90
• In Vitro Model: NBLW-R cells; Brain; Homo sapiens (Human); CVCL_VJ91
• Experiment for Molecule Alteration: Sangersequencing assay; Targeted deep sequencing assay
• Experiment for Drug Resistance: Array CGH assay
• Mechanism Description: Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: ALK tyrosine kinase receptor (ALK) [25]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L
• Resistant Drug: Crizotinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ALK signaling pathway; Activation; hsa05200
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: NCI-H3122 cells; Lung; Homo sapiens (Human); CVCL_5160
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: Direct sequencing assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: There is a C to G mutation (asterix) in codon 3522 in exon 23 resulting in the F1174L mutation. When present in cis with an ALk translocation, this mutation (also detected in neuroblastomas) causes an increase in ALk phosphorylation, cell growth and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib mediated downregulation of ALk signaling and blocks apoptosis in RANBP2-ALk Ba/F3 cells.

Cyclophosphamide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-129 [26]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cyclophosphamide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell cycle; Inhibition; hsa04110
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: BE-M17 cells; Adrenal; Homo sapiens (Human); N.A.
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: NB-1643 cells; Adrenal; Homo sapiens (Human); CVCL_5627
• In Vitro Model: NB1 cells; Adrenal; Homo sapiens (Human); CVCL_1440
• In Vitro Model: NBSD cells; Adrenal; Homo sapiens (Human); CVCL_LF68
• In Vitro Model: Neuro-2a cells; Adrenal; Homo sapiens (Human); CVCL_0470
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: Sk-N-SH cells; Adrenal; Homo sapiens (Human); CVCL_0531
• In Vitro Model: Sk-SY-5Y cells; Adrenal; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-129 suppressed cell growth and potentiated chemosensitivity by inhibiting MYO10.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Unconventional myosin-X (MYO10) [26]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cyclophosphamide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: BE-M17 cells; Adrenal; Homo sapiens (Human); N.A.
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: NB-1643 cells; Adrenal; Homo sapiens (Human); CVCL_5627
• In Vitro Model: NB1 cells; Adrenal; Homo sapiens (Human); CVCL_1440
• In Vitro Model: NBSD cells; Adrenal; Homo sapiens (Human); CVCL_LF68
• In Vitro Model: Neuro-2a cells; Adrenal; Homo sapiens (Human); CVCL_0470
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: Sk-N-SH cells; Adrenal; Homo sapiens (Human); CVCL_0531
• In Vitro Model: Sk-SY-5Y cells; Adrenal; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-129 suppressed cell growth and potentiated chemosensitivity by inhibiting MYO10.

Dabrafenib/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [27]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [28]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600D (c.1799_1800delTGinsAC)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: Brain; .

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [27]

• Sensitive Disease: Pleomorphic xanthoastrocytoma [ICD-11: 2A00.0Y]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Dabrafenib/Trametinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: Brain; .

Dacarbazine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dacarbazine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dacarbazine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dacarbazine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [29]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Athymic nu/nu female mice xenograft model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Protein kinase C signaling pathways; Inhibition; hsa04310
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: On the other hand, the frequency of LDR that we noted for paclitaxel (20%) and vincristine (20%) was similar to the clinical response rates for these compounds. These data suggest that although MDR1 expression by glial tumors may not be the dominant direct cellular process responsible for tumor resistance to natural products, other mechanisms are present that diminish their activity. The clinical mechanisms of natural product resistance may be a multifactorial function of endothelial expression of MDR1 at the blood-brain barrier in conjunction with glial tumor cell expression of alternative efflux pumps, such as MRP, altered tubulin with lower affinity binding sites, and/or protein kinase C signaling pathways that suppress apoptosis.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Docetaxel
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: piR-hsa-39980 [30]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: piR-39980 is an oncogenic piRNA overexpressed in NB cells which induces the cancer cell growth, enhance metastasis, and inhibit the cellular senescence by targeting JAk3 as well as desensitizes the chemotherapeutic drug. And piR-39980 was found to desensitize the effect of doxorubicin and inhibit drug-induced apoptosis.

Key Molecule: hsa-mir-125b [31]

• Resistant Disease: Primitive neuroectodermal tumor [ICD-11: 2A00.08]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK3 (JAK3) [30]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• Experiment for Molecule Alteration: Dual-luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: piR-39980 is an oncogenic piRNA overexpressed in NB cells which induces the cancer cell growth, enhance metastasis, and inhibit the cellular senescence by targeting JAk3 as well as desensitizes the chemotherapeutic drug. And piR-39980 was found to desensitize the effect of doxorubicin and inhibit drug-induced apoptosis.

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [31]

• Resistant Disease: Primitive neuroectodermal tumor [ICD-11: 2A00.08]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-127 [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: hsa-mir-21 [33]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay
• Mechanism Description: To validate the possible association of miR-21 with drug resistance of T98G cells, we transfected anti-miR-21 inhibitor into the cells. The expression level of miR-21 was significantly lower in T98G transfected cells (than in the parental control cells). Transfected cells showed a high apoptotic rate compared to control after Dox treatment by TUNEL assay, suggesting that combined Dox and miR-21 inhibitor therapy can sensitize GBM resistant cells to anthracyclines by enhancing apoptosis.

Key Molecule: hsa-mir-137 [34]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: UkF-NB3 cells; Bone marrow; Homo sapiens (Human); CVCL_9904
• In Vivo Model: Immunodeficient NCr nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell titer glo assay assay
• Mechanism Description: Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: Cellular tumor antigen p53 (TP53) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: Runt-related transcription factor 2 (RUNX2) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: Baculoviral IAP repeat-containing protein 5 (BIRC5) [32]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: microRNA-127 silencing significantly affects cell growth and increases the sensitivity to adriamycin. microRNA-127 silencing arrests the cell cycle, potentiates adriamycin-induced apoptosis, and increases cellular Rh-123 uptake. microRNA-127 silencing down-regulates MDR1, MRP1, Runx2, Bcl-2, Survivin and ErbB4 expression while up-regulates p53 expression. microRNA-127 silencing inhibits AkT phosphorylation.

Key Molecule: Nuclear receptor subfamily 1 group I3 (NR1I3) [34]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: UkF-NB3 cells; Bone marrow; Homo sapiens (Human); CVCL_9904
• In Vivo Model: Immunodeficient NCr nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell titer glo assay assay
• Mechanism Description: Hypermethylation of the miR-137 promoter and negative regulation of miR-137 by CAR contribute in part to reduced miR-137 expression and increased CAR and MDR1 expression in doxorubicin-resistant neuroblastoma cells.

Key Molecule: Forkhead box protein M1 (FOXM1) [35]

• Sensitive Disease: Rhabdoid tumor [ICD-11: 2A00.0Y]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Tm87-16 cells; Kidney; Homo sapiens (Human); CVCL_8001
• In Vitro Model: TTC549 cells; Liver; Homo sapiens (Human); CVCL_8005
• In Vitro Model: STM91-01 cells; Lung; Homo sapiens (Human); CVCL_8000
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: FOXM1 siRNA and FOXM1 inhibitor (thiostrepton) successfully downregulated the mRNA and protein expression of FOXM1 in vitro and the downregulation of FOXM1 inhibited cell proliferation, drug resistance to doxorubicin, migration, invasion, and caused the cell cycle arrest and apoptosis of MRT cell lines.

Entrectinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [36]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1245V (c.3733T>G)
• Sensitive Drug: Entrectinib
• Experimental Note: Identified from the Human Clinical Data

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125b [31]

• Resistant Disease: Primitive neuroectodermal tumor [ICD-11: 2A00.08]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Resistant Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: Cisplatin and etoposide are both substrates for membrane-bound efflux pumps, such as MRP and MDR1, which prevent their entry into the extracellular space of the central nervous system. The low levels of in vitro drug resistance noted for cisplatin and etoposide may be explained in part by the absence of such a barrier in our in vitro assay system.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [31]

• Resistant Disease: Primitive neuroectodermal tumor [ICD-11: 2A00.08]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-296-3p [38]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Key Molecule: hsa-mir-204 [23]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Sensitive Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Sensitive Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Potassium voltage-gated channel subfamily H member 1 (KCNH1) [38]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [23]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Key Molecule: BDNF/NT-3 growth factors receptor (NTRK2) [23]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Etoposide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vivo Model: Orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-204 direct targeting of the 3' UTR of BCL2 and NTRk2 (TrkB). BCL2 has a critical role in ensuring the survival of early developing cell types, NTRk2 is also a well-established pro-survival oncogene in neuroblastoma, signalling the activation of the PI3k/AkT pathway, a significant mechanism of drug resistance in neuroblastoma. Ectopic miR-204 expression significantly increased sensitivity to cisplatin and etoposide in vitro.

Imatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-203 [39]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: SNAI2 is a direct target of miR-203 and that miR-203-mediated inhibition of SNAI2 is dependent on a conversed motif in the 3'-UTR of SNAI2. Recent independent studies have shown that overexpression of SNAI2 alters cell invasion, motility, chemoresistance, metastasis and poor prognosis in several human cancers. As a member of the snail family of transcription factors, SNAI2 can repress E-cadherin transcription and induce EMT directly. Therefore, SNAI2 overexpression due to reduction of miR-203 may result in EMT and chemoresistance in GBM via these pathways. Additionally, miR-203 may relieve E-cadherin from transcriptional repression by targeting SNAI2 signaling. Nevertheless, because one single miRNA might have multiple targets, judicious considerations are essential for identi cation of the main functional targets.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Zinc finger protein SNAI2 (SNAI2) [39]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: SNAI2 is a direct target of miR-203 and that miR-203-mediated inhibition of SNAI2 is dependent on a conversed motif in the 3'-UTR of SNAI2. Recent independent studies have shown that overexpression of SNAI2 alters cell invasion, motility, chemoresistance, metastasis and poor prognosis in several human cancers. As a member of the snail family of transcription factors, SNAI2 can repress E-cadherin transcription and induce EMT directly. Therefore, SNAI2 overexpression due to reduction of miR-203 may result in EMT and chemoresistance in GBM via these pathways. Additionally, miR-203 may relieve E-cadherin from transcriptional repression by targeting SNAI2 signaling. Nevertheless, because one single miRNA might have multiple targets, judicious considerations are essential for identi cation of the main functional targets.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-296-3p [38]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Potassium voltage-gated channel subfamily H member 1 (KCNH1) [38]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Imatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Irinotecan

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Irinotecan
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Irinotecan
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Irinotecan
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Lorlatinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [1]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L
• Resistant Drug: Lorlatinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NBLW cells; Brain; Homo sapiens (Human); CVCL_VJ90
• In Vitro Model: NBLW-R cells; Brain; Homo sapiens (Human); CVCL_VJ91
• Experiment for Molecule Alteration: Sangersequencing assay; Targeted deep sequencing assay
• Experiment for Drug Resistance: Array CGH assay
• Mechanism Description: Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.

Maraviroc

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: C-C motif chemokine receptor 5 (CCR5) [40]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Function; Inhibition
• Sensitive Drug: Maraviroc
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: CCL5-CCR5 signaling pathway; Inhibition; has05163
• In Vivo Model: Intracranial GBM patient-derived xenograft model; Mus musculus
• Experiment for Molecule Alteration: Neutral comet assay; ELISA assay; Immunofluorescence staining analysis; Immunohistochemistry staining analysi; Immunoblot assay
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: The authors uncovered that pericytes potentiate DNA damage repair (DDR) in GBM cells residing in the perivascular niche, which induces temozolomide (TMZ) chemoresistance. Disrupting CCL5-CCR5 paracrine signaling through the brain-penetrable CCR5 antagonist maraviroc (MVC) potently inhibits pericyte-promoted DDR and effectively improves the chemotherapeutic efficacy of TMZ.

Matrine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa_circ_104075 [41]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Matrine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell growth; Activation; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin/PI3K/AKT signaling pathway; Inhibition; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Matrine inhibits Bcl-9 expression through down-regulating circRNA-104075 expression in U251 cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: B-cell CLL/lymphoma 9 protein (BCL9) [41]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Matrine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Wnt/Beta-catenin/PI3K/AKT signaling pathway; Inhibition; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Matrine inhibits Bcl-9 expression through down-regulating circRNA-104075 expression in U251 cells.

Meclizine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [42]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Meclizine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-1-V4 cells; Esophagus; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: GBM stem cells (GBMSC) resist the standard-of-care therapy, temozolomide, and are considered a major contributor to tumor resistance. GBMSCs are resistant to the standard-of-care temozolomide therapy, but temozolomide supplemented with tight-binding piperazine meclizine and flunarizine greatly enhanced GBMSC death over temozolomide alone.

Mestranol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [2]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Mestranol
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: MDCK cells; Kidney; Canis lupus familiaris (Dog) (Canis familiaris); CVCL_0422
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Methotrexate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Resistant Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Sensitive Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Sensitive Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Mitomycin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Melanoma-associated antigen 12 (MAGEA12) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 2 (MAGEA2) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 3 (MAGEA3) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Key Molecule: Melanoma-associated antigen 6 (MAGEA6) [24]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Mitomycin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: UW228 cells; Brain; Homo sapiens (Human); CVCL_8585
• In Vitro Model: R262 cells; Bone marrow; Homo sapiens (Human); CVCL_VU83
• In Vitro Model: R300 cells; Bone marrow; Homo sapiens (Human); CVCL_VU84
• In Vitro Model: UW426 cells; Bone marrow; Homo sapiens (Human); CVCL_DH82
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The repression of MAGE-A by miR-34a results in increased expression of p53 thus lead to resistance.

Nivolumab

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mismatch repair endonuclease PMS2 (PMS2) [43]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: FS-deletion; p.K706fs*19 (c.2118delG)
• Sensitive Drug: Nivolumab
• Experimental Note: Identified from the Human Clinical Data

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-34 [44]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR34a/PD-L1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U87-P cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V/PI apoptosis assay; Cell cycle assay; MTT assay
• Mechanism Description: miR34a attenuates glioma cells progression and chemoresistance via targeting PD-L1.

Key Molecule: hsa-mir-21 [45]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: EGFR/STAT3 signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The miR-21 inhibitor could enhance the chemo-sensitivity of human glioblastoma cells to taxol. A combination of miR-21 inhibitor and taxol could be an effective therapeutic strategy for controlling the growth of GBM by inhibiting STAT3 expression and phosphorylation.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death 1 ligand 1 (PD-L1) [44]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR34a/PD-L1 signaling pathway; Regulation; hsa05206
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U87-P cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: Annexin V/PI apoptosis assay; Cell cycle assay; MTT assay
• Mechanism Description: miR34a attenuates glioma cells progression and chemoresistance via targeting PD-L1.

Panobinostat

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Quinolinate phosphoribosyltransferase (QPRT) [46]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Panobinostat
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: ES-2 cells; Ovary; Homo sapiens (Human); CVCL_3509
• In Vitro Model: MG-63 cells; Bone; Homo sapiens (Human); CVCL_0426
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vitro Model: MOLM-14 cells; Peripheral blood; Homo sapiens (Human); CVCL_7916
• In Vitro Model: SH-1-V8 cells; Esophagus; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis; RNA-sequencing analysis
• Experiment for Drug Resistance: Flow cytometry
• Mechanism Description: RNA-sequencing identifies quinolinic acid phosphoribosyltransferase (QPRT) as a highly expressed gene in bortezomib-panobinostat resistant U87 cells. QPRT, an enzyme catalyzing the rate-determining conversion of quinolinic acid (QA) to nicotinic acid mononucleotide (NAMN) a precursor for de novo NAD+ biosynthesis from tryptophan.

Perphenazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Perphenazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The present study explored the effects of perphenazine and prochlorperazine on the levels of ABCB1, ABCG2, E-cadherin, alpha-tubulin and integrins (alpha3, alpha5, and beta1), as well as on the migratory and invasive ability of U87-MG cells. The results suggested that perphenazine and prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Perphenazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The present study explored the effects of perphenazine and prochlorperazine on the levels of ABCB1, ABCG2, E-cadherin, alpha-tubulin and integrins (alpha3, alpha5, and beta1), as well as on the migratory and invasive ability of U87-MG cells. The results suggested that perphenazine and prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Integrin alpha-3 (ITA3) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Perphenazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The present study explored the effects of perphenazine and prochlorperazine on the levels of ABCB1, ABCG2, E-cadherin, alpha-tubulin and integrins (alpha3, alpha5, and beta1), as well as on the migratory and invasive ability of U87-MG cells. The results suggested that perphenazine and prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Key Molecule: Integrin beta-1 (ITGB1) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Perphenazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis
• Mechanism Description: The present study explored the effects of perphenazine and prochlorperazine on the levels of ABCB1, ABCG2, E-cadherin, alpha-tubulin and integrins (alpha3, alpha5, and beta1), as well as on the migratory and invasive ability of U87-MG cells. The results suggested that perphenazine and prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Picrotoxin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Gamma-aminobutyric acid receptor subunit alpha-1 (GABAARs) [48]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Function; Inhibition
• Resistant Drug: Picrotoxin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SH-1-V7 cells; Esophagus; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole-cell patch-clamp recording assay
• Experiment for Drug Resistance: Slice whole-cell recording
• Mechanism Description: Receptors containing Delta T6'Y had marginally weaker sensitivity to positive allosteric modulators, likely a secondary consequence of differing GABA sensitivity. Overexpression of DeltaT6'Y in neurons resulted in robust PTX-insensitive IPSCs, suggesting that Delta-containing receptors are readily recruited by synaptically released GABA.

Prochlorperazine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Prochlorperazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis; RNA-sequencing analysis
• Experiment for Drug Resistance: Wound healing assay;Transwell assay
• Mechanism Description: Prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Prochlorperazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis; RNA-sequencing analysis
• Experiment for Drug Resistance: Wound healing assay;Transwell assay
• Mechanism Description: Prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Integrin alpha-3 (ITA3) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Prochlorperazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis; RNA-sequencing analysis
• Experiment for Drug Resistance: Wound healing assay;Transwell assay
• Mechanism Description: Prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Key Molecule: Integrin beta-1 (ITGB1) [47]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Prochlorperazine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: SHI-1 cells; Bone marrow; Homo sapiens (Human); CVCL_2191
• Experiment for Molecule Alteration: Western blotting analysis; RNA-sequencing analysis
• Experiment for Drug Resistance: Wound healing assay;Transwell assay
• Mechanism Description: Prochlorperazine may modulate the expression levels of multidrug resistance proteins (they decreased ABCB1 and increased ABCG2 expression), E-cadherin, alpha-tubulin and integrins, and could impair the migration and invasion of U-87 MG cells.

Rabeprazole

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Vimentin (VIM) [49]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Rabeprazole
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: AKT/GSK3beta signaling pathway; Inhibition; hsa04931
• Cell Pathway Regulation: NF-KappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: MDA-231 cells; Pleural effusion; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MJ cells; Peripheral blood; Homo sapiens (Human); CVCL_1414
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vivo Model: Male Wistar rats-Stereotaxic glioma model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; Gene expression analysis
• Experiment for Drug Resistance: MTT assay; Scratch wound healing migration assay; Transwell invasion assay
• Mechanism Description: Epithelial to mesenchymal transition (EMT) is pivotal in embryonic development and wound healing, whereas in cancer it inflicts malignancy and drug resistance. Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition. Rabeprazole suppressed EMT by impeding AKT/GSK3beta phosphorylation and/or NF-kappaB signaling and sensitized temozolomide resistance.

Key Molecule: Dishevelled binding antagonist of beta catenin 1 (DACT1) [49]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Rabeprazole
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: AKT/GSK3beta signaling pathway; Inhibition; hsa04931
• Cell Pathway Regulation: NF-KappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: MDA-231 cells; Pleural effusion; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MJ cells; Peripheral blood; Homo sapiens (Human); CVCL_1414
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vivo Model: Male Wistar rats-Stereotaxic glioma model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis; Gene expression analysis
• Experiment for Drug Resistance: MTT assay; Scratch wound healing migration assay; Transwell invasion assay
• Mechanism Description: Epithelial to mesenchymal transition (EMT) is pivotal in embryonic development and wound healing, whereas in cancer it inflicts malignancy and drug resistance. Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition. Rabeprazole suppressed EMT by impeding AKT/GSK3beta phosphorylation and/or NF-kappaB signaling and sensitized temozolomide resistance.

Key Molecule: Glial fibrillary acidic protein (GFAP) [49]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Rabeprazole
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: AKT/GSK3beta signaling pathway; Inhibition; hsa04931
• Cell Pathway Regulation: NF-KappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: MDA-231 cells; Pleural effusion; Homo sapiens (Human); CVCL_0062
• In Vitro Model: MJ cells; Peripheral blood; Homo sapiens (Human); CVCL_1414
• In Vitro Model: MMQ cells; Pituitary gland; Rattus norvegicus (Rat); CVCL_2117
• In Vitro Model: MOLM-13 cells; Peripheral blood; Homo sapiens (Human); CVCL_2119
• In Vivo Model: Male Wistar rats-Stereotaxic glioma model; Rattus norvegicus
• Experiment for Molecule Alteration: Western blotting analysis; Gene expression analysis
• Experiment for Drug Resistance: MTT assay; Scratch wound healing migration assay; Transwell invasion assay
• Mechanism Description: Epithelial to mesenchymal transition (EMT) is pivotal in embryonic development and wound healing, whereas in cancer it inflicts malignancy and drug resistance. Rabeprazole has efficacy per se and reduces resistance to temozolomide in glioma via EMT inhibition. Rabeprazole suppressed EMT by impeding AKT/GSK3beta phosphorylation and/or NF-kappaB signaling and sensitized temozolomide resistance.

Talazoparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [50]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: Talazoparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [50]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: Talazoparib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: IDH1 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Female athymic nu/nu mouse PDX model; Mus musculus
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The oncometabolite, 2-hydroxyglutarate, renders IDH1/2 mutant cancer cells deficient in homologous recombination and confers vulnerability to synthetic lethal targeting with PARP inhibitors.

Temozolomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: GSTP1 is the first major mechanism of resistance alkylator agents encounter after entering the cancer cell cytoplasm. GSTP1 acts to enzymatically conjugate glutathione to the reactive metabolites of BCNU. The mechanisms by which GSTP1 may be up-regulated in gliomas are under investigation. Constitutive expression is thought to be influenced by the proximal promoter factor Sp1, whereas increased expression levels may result from stabilization of GSTP1 mRNA. GSTP1 expression has been reported to be induced by drug exposure, indicating that it may play a role in acquired drug resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-20b-3p [51]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: LncRNA regulator of Akt signaling associated with HCC and RCC (LNCARSR) [51]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: hsa-miR-20b-3p [51]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: Cancer susceptibility 2 (CASC2) [52], [53]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. CASC2 is downregulated in gliomas, resulting in increased miR193a-5p level and a decrease in mTOR expression, which further induces protective autophagy, leading to TMZ resistance.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [54], [55]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR203-TS signaling pathway; Regulation; hsa05206
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR203 and down-regulating TS expression. MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by upregulating ZEB1.

Key Molecule: hsa-mir-132 [56]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U87MG-res cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Soft agar assay; MTT assay; Sphere formation assay
• Mechanism Description: microRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma.

Key Molecule: hsa-mir-29c [57]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; RIP assay; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR29c via SP1 and MGMT. XIST expression was up-regulated by miR29c inhibition while down-regulated by ectopic miR29, and XIST directly binds to miR29c to inhibit its expression, XIST and miR29c neatively regulates each other.

Key Molecule: X inactive specific transcript (XIST) [57]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Key Molecule: hsa-mir-223 [58]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Transwell assay; Transwell matrix penetration assay; MTT assay; BrdU incorporation assay
• Mechanism Description: miR223/PAX6 axis regulates glioblastoma stem cell proliferation and the chemo resistance to TMZ via inhibition of PI3k/Akt pathway.

Key Molecule: hsa-mir-181a [52]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: LncRNA CASC2 interacts with miR181a to modulate glioma growth and resistance to TMZ through PTEN pathway.

Key Molecule: hsa-mir-497 [59]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Activation; hsa04212
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: SF295 cells; Brain; Homo sapiens (Human); CVCL_1690
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2. The silencing of miR-497 decreased the protein levels of IGF1R/IRS1 pathway-related proteins, that is, IGF1R, IRS1, mTOR, and Bcl-2.

Key Molecule: hsa-mir-195 [60]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Hsa-miR-195 could negatively regulate the expression of CCNE1 in glioma and microRNA-195 reverses the resistance to temozolomide through targeting cyclin E1 in glioma cells.

Key Molecule: hsa-mir-151a [61]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Inhibiting miR-151a leads to increased XRCC4 levels, resulting in activated DNA repair and subsequent resistance to TMZ.

Key Molecule: hsa-mir-101 [62]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expressiom; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [62]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: hsa-miR-634 [63]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: RAF/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of CYR61 increased the survival rate of U251/TMZ and U87/TMZ cells after TMZ treatment, while induction of miR-634 significantly suppressed the survival of U251/TMZ and U87/TMZ cells after TMZ treatment.

Key Molecule: hsa-mir-10a [64]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregulation of TUSC7,which acted by directly targeting and silencing expression of miR-10a gene, suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells,, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells.

Key Molecule: Tumor suppressor candidate 7 (TUSC7) [64]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregulation of TUSC7,which acted by directly targeting and silencing expression of miR-10a gene, suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells,, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells.

Key Molecule: hsa-miR-423-5p [65]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: N3 GBM cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Cell-cycle assay
• Mechanism Description: miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [66]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: hsa-mir-138 [67]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR138/BIM signaling pathway; Regulation; hsa05206
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vitro Model: D247MG cells; Brain; Homo sapiens (Human); CVCL_1153
• In Vitro Model: LN-319 cells; Brain; Homo sapiens (Human); CVCL_3958
• In Vitro Model: LN-428 cells; Brain; Homo sapiens (Human); CVCL_3959
• In Vivo Model: BALB/c nu/nu nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype.

Key Molecule: hsa-mir-16 [68]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The mechanism responsible for resistance of glioma cells to temozolomide was associated with miR-16-mediated downregulation of Bcl-2. miR-16 may function as an important modifier of the response of glioma cells to temozolomide.

Key Molecule: hsa-mir-497 [69]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Ectopic overexpression of miR-497 promotes chemotherapy resistance in glioma cells by targeting PDCD4, a tumor suppressor that is involved in apoptosis. In contrast, the inhibition of miR-497 enhances apoptosis and increases the sensitivity of glioma cells to TMZ.

Key Molecule: hsa-mir-125b-2 [70]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Inhibition; hsa04210
• In Vitro Model: Human glioblastoma tissues and PRGMTTT samples; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-125b-2 is overexpressed in glioblastoma multiforme tissues and the corresponding stem cells (GBMSC); downregulation of miR-125b-2 expression in GBMSC could allow TMZ to induce GBMSC apoptosis. Additionally, the expression of the anti-apop-totic protein Bcl-2 was decreased after the TMZ+miR-125b-2 inhibitor treatment, while the expression of the proapoptotic protein Bax was increased. he induction of apoptosis in GBMSC is also associated with increased cytochrome c release from mitochondria, induction of Apaf-1, activation of caspase-3 and poly-ADP-ribose polymerase (PARP). miR-125b-2 overexpression might confer glioblastoma stem cells resistance to TMZ.

Key Molecule: hsa-mir-21 [71]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: miR-21 could inhibit TMZ-induced apoptosis in U87MG cells, at least in part, by decreasing Bax/Bcl-2 ratio and caspase-3 activity.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [64]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Upregulation of TUSC7,which acted by directly targeting and silencing expression of miR-10a gene, suppressed both TMZ resistance and expression of multidrug resistance protein 1 (MDR1) in U87TR cells,, and miR-10a mediated TUSC7-induced inhibition on TMZ resistance in U87TR cells.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [66]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [66]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [66]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Knockdown of long noncoding RNA H19 sensitizes human glioma cells to temozolomide therapy.the expression level of H19 transcripts was increased compared to wild-type or nonresistant clones.Furthermore, the reduced expression of H19 altered major drug resistance genes, such as ABCB1 (MDR1), ABCC (MRP), and ABCG2 (BCRP), both at the mRNA and protein levels. Taken together, these findings suggest that H19 plays an important role in the development of TMZ resistance, and may represent a novel therapeutic target for TMZ-resistant gliomas.Our results suggested that knockdown of H19 significantly downregulated the expression of these drug-resistant genes, both at the mRNA (P<0.001 vs respective control siRNA) and protein levels. These data confirm that the H19-induced TMZ resistance is in part mediated by MDR, MRP, and ABCG2.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [72]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: Glioblastoma tissue; .
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Patient survival time
• Mechanism Description: In the chemosensitive MDR1-negative parental cell line k562 10 ug/ml temozolomide resulted in pronounced cell death with only 47.1% surviving 48 h compared with the control. In contrast, in the highly MDR1-expressing resistant subline k562-VP16, cell death was significantly lower after exposure to temozolomide with 73.4% surviving 48 h (P = 0.002). Addition of a nontoxic dose of the MDR1-modulator cyclosporine A (1 uM) to temozolomide resulted in a trend towards restoration of chemosensitivity in the resistant MDR1-expressing cell line.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: SBF2 antisense RNA 1 (SBF2-AS1) [73]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: NF-kB/XIAP signaling pathway; Activation; hsa04218
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Subcutaneous and orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exosomal SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells.

Key Molecule: hsa-miR-151a-3p [73]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• Cell Pathway Regulation: miR151a-3p/XRCC4 signaling pathway; Regulation; hsa05206
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Subcutaneous and orthotopic xenograft model; Mus musculus
• Experiment for Molecule Alteration: RIP experiments; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Exosomal SBF2-AS1 functions as a ceRNA for miR-151a-3p, leading to the disinhibition of its endogenous target, X-ray repair cross complementing 4 (XRCC4), which enhances DSB repair in GBM cells. Exosomes selected from temozolomide-resistant GBM cells had high levels of SBF2-AS1 and spread TMZ resistance to chemoresponsive GBM cells.

Key Molecule: H19, imprinted maternally expressed transcript (H19) [74]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Silencing of H19 decreases chemoresistance through suppressing EMT via the Wnt/beta-Catenin pathway.

Key Molecule: Vimentin (VIM) [74]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: Western blot analysis; RNAi assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Silencing of H19 decreases chemoresistance through suppressing EMT via the Wnt/beta-Catenin pathway.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [74]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• Experiment for Molecule Alteration: Western blot analysis; RNAi assay
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Silencing of H19 decreases chemoresistance through suppressing EMT via the Wnt/beta-Catenin pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hepatocyte growth factor receptor (MET) [51]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: Hepatocyte growth factor receptor (MET) [51]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: c-Met signaling signaling pathway; Inhibition; hsa01521
• In Vitro Model: HG7 cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: Lnc-TALC promotes O6-methylguanine-DNA methyltransferase expression via regulating the c-Met pathway by competitively binding with miR-20b-3p.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [53]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Cell cytotoxicity; Activation; hsa04650
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. CASC2 is downregulated in gliomas, resulting in increased miR193a-5p level and a decrease in mTOR expression, which further induces protective autophagy, leading to TMZ resistance.

Key Molecule: Tumor suppressor candidate 3 (TUSC3) [56]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: U87MG-res cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Immunofluorescence staining; Western blot analysis
• Experiment for Drug Resistance: Soft agar assay; MTT assay; Sphere formation assay
• Mechanism Description: microRNA-132 induces temozolomide resistance and promotes the formation of cancer stem cell phenotypes by targeting tumor suppressor candidate 3 in glioblastoma.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [57]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Key Molecule: Transcription factor Sp1 (SP1) [57]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA damage repair signaling pathway; Activation; hsa03410
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST was inversely correlated with miR29c, positively correlated with PS1, positively related with MGMT. XIST can inhibit miR29c expression by directly binding to miR29c and subsequently up-regulate the expression of SP1 and MGMT to promote the chemoresistance of glioma cells to TMZ.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [55]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: MALAT1 decreased the sensitivity of resistant glioma cell lines to TMZ by upregulating ZEB1.

Key Molecule: Paired box protein Pax-6 (PAX6) [58]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Transwell assay; Transwell matrix penetration assay; MTT assay; BrdU incorporation assay
• Mechanism Description: miR223/PAX6 axis regulates glioblastoma stem cell proliferation and the chemo resistance to TMZ via inhibition of PI3k/Akt pathway.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [59]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Activation; hsa04212
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: SF295 cells; Brain; Homo sapiens (Human); CVCL_1690
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2. The silencing of miR-497 decreased the protein levels of IGF1R/IRS1 pathway-related proteins, that is, IGF1R, IRS1, mTOR, and Bcl-2.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [59]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: IGF1R/IRS1 signaling pathway; Activation; hsa04212
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: HEK293 cells; Kidney; Homo sapiens (Human); CVCL_0045
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vitro Model: LN382 cells; Brain; Homo sapiens (Human); CVCL_3956
• In Vitro Model: SF295 cells; Brain; Homo sapiens (Human); CVCL_1690
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Up-regulation of miR-497 confers resistance to temozolomide in human glioma cells by targeting mTOR/Bcl-2. The silencing of miR-497 decreased the protein levels of IGF1R/IRS1 pathway-related proteins, that is, IGF1R, IRS1, mTOR, and Bcl-2.

Key Molecule: G1/S-specific cyclin-E1 (CCNE1) [60]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Hsa-miR-195 could negatively regulate the expression of CCNE1 in glioma and microRNA-195 reverses the resistance to temozolomide through targeting cyclin E1 in glioma cells.

Key Molecule: DNA repair protein XRCC4 (XRCC4) [61]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Inhibiting miR-151a leads to increased XRCC4 levels, resulting in activated DNA repair and subsequent resistance to TMZ.

Key Molecule: CCN family member 1 (CYR61) [63]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• Cell Pathway Regulation: RAF/ERK signaling pathway; Activation; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Overexpression of CYR61 increased the survival rate of U251/TMZ and U87/TMZ cells after TMZ treatment, while induction of miR-634 significantly suppressed the survival of U251/TMZ and U87/TMZ cells after TMZ treatment.

Key Molecule: Growth protein 4 inhibitor (ING4) [65]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: N3 GBM cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell-cycle assay
• Mechanism Description: miR-423-5p contributes to a malignant phenotype and temozolomide chemoresistance in glioblastomas.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [67]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: miR138/BIM signaling pathway; Regulation; hsa05206
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vitro Model: D247MG cells; Brain; Homo sapiens (Human); CVCL_1153
• In Vitro Model: LN-319 cells; Brain; Homo sapiens (Human); CVCL_3958
• In Vitro Model: LN-428 cells; Brain; Homo sapiens (Human); CVCL_3959
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Transient transfection of miR-138 mimics in glioma cells with low basal miR-138 expression increased glioma cell proliferation. Moreover, miR-138 overexpression increased TMZ resistance in long-term glioblastoma cell lines and glioma initiating cell cultures. The apoptosis regulator BIM was identified as a direct target of miR-138, and its silencing mediated the induced TMZ resistance phenotype.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [68]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: The mechanism responsible for resistance of glioma cells to temozolomide was associated with miR-16-mediated downregulation of Bcl-2. miR-16 may function as an important modifier of the response of glioma cells to temozolomide.

Key Molecule: Programmed cell death protein 4 (PDCD4) [69]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Ectopic overexpression of miR-497 promotes chemotherapy resistance in glioma cells by targeting PDCD4, a tumor suppressor that is involved in apoptosis. In contrast, the inhibition of miR-497 enhances apoptosis and increases the sensitivity of glioma cells to TMZ.

Key Molecule: DNA mismatch repair protein Msh6 (MSH6) [75]

• Resistant Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Mutation; .
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: SSCP assay; Direct sequencing assay
• Mechanism Description: Prominent example of therapy-induced molecular alterations in gliomas which themselves ensue therapeutic consequences are MSH6 mutations in glioblastomas which arise during temozolomide chemotherapy and which are able to convey temozolomide resistance in affected tumors.

Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [76]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: UPR signaling pathway; Activation; hsa0414)
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nu/nu athymic mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Transcripts for the ER chaperones GRP94 and GRP78 were upregulated in the U87MG and U87+EGFR gliomas, relative to normal mouse brain from healthy animals. Elevated levels of UPR transcription factors and ER chaperones correlated with poor patient prognosis; western blots of high grade gliomas and tissue microarray immunohistochemistry verified high expression of UPR players, especially GRP94, in high grade gliomas. Activation of the UPR signaling pathways is a prominent feature of glioma biology that leads to metabolic shifts and enhances chemoresistant features of gliomas.

Key Molecule: Endoplasmin (HSP90B1) [76]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: UPR signaling pathway; Activation; hsa0414)
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nu/nu athymic mice xenografts model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: Clonogenic assay
• Mechanism Description: Transcripts for the ER chaperones GRP94 and GRP78 were upregulated in the U87MG and U87+EGFR gliomas, relative to normal mouse brain from healthy animals. Elevated levels of UPR transcription factors and ER chaperones correlated with poor patient prognosis; western blots of high grade gliomas and tissue microarray immunohistochemistry verified high expression of UPR players, especially GRP94, in high grade gliomas. Activation of the UPR signaling pathways is a prominent feature of glioma biology that leads to metabolic shifts and enhances chemoresistant features of gliomas.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: For drugs that have evaded cytosolic mechanisms of drug resistance, the nucleus is equipped with the capacity to remove BCNU or temozolomide alkyl groups from the O6-position of guanine via a reaction catalyzed by MGMT. Repair occurs before cross-link formation and involves an irreversible stoichiometric covalent transfer of the O6-alkyl DNA adduct to a cysteine within the active site of MGMT, resulting in the inactivation and subsequent depletion of enzyme activity. MGMT-mediated repair is rapid, with a half-life of 35 hours. MGMT enzyme recovery occurs via de novo synthesis. In malignant glioma patients, MGMT overexpression has been associated with resistance to BCNU and similar alkylating agents and was an independent predictor of poor survival. MGMT is also thought to contribute to temozolomide resistance, which we did not detect in our study. This may be related to the in vitro pharmacokinetic differences between BCNU and temozolomide.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-126-3p [77]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell autophagy; Inhibition; hsa04140
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: miR-126-3p sensitizes glioblastoma cells to temozolomide by inactivating Wnt/beta-catenin signaling via targeting SOX2.

Key Molecule: hsa-mir-23b [78]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U87 GSCs; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-23b overexpression sensitized U87 glioma stem cells to TMZ-induced growth inhibition. And miR-23b had a synergistically suppressive effect on the expression of HMGA2 with TMZ in U87 GSCs.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [79]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87-luc2; Brain; Homo sapiens (Human); CVCL_5J12
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: XTT assay; CellTiter-Glo Luminescent Cell Viability Assay
• Mechanism Description: Targeted nanocomplex carrying siRNA against MALAT1 sensitizes glioblastoma to temozolomide.

Key Molecule: Cancer susceptibility 2 (CASC2) [53]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: CASC2 negatively regulates miR193a-5p expression by direct interaction in glioma cells. Overexpression of CASC2 or inhibition of miR193a-5p reduced TMZ-induced autophagy via mTOR upregulation, which makes the glioma cells become sensitive to TMZ cytotoxicity.

Key Molecule: hsa-miR-193a-5p [53]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. mTOR or CASC2 overexpression or miR193a-5p inhibition remarkably reduced autophagy-related proteins expression.

Key Molecule: hsa-miR-146b-5p [80]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/NF-kappaB signaling pathway; Inhibition; hsa05135
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 146b 5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6. Overexpression of miR 146b 5p or TRAF6 knockdown significantly decreased the level of p AkT and p p65.

Key Molecule: hsa-mir-29c [57]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qRT-PCR; RIP assay; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR29c via SP1 and MGMT. XIST/miR29c axis regulated glioma cell chemoresistance to TMZ through RNA mismatch repair pathway. XIST expression was up-regulated by miR29c inhibition while down-regulated by ectopic miR29, and XIST directly binds to miR29c to inhibit its expression, XIST and miR29c neatively regulates each other.

Key Molecule: X inactive specific transcript (XIST) [57]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: XIST can amplify the chemoresistance of glioma cell lines to TMZ through directly targetting miR29c via SP1 and MGMT. XIST/miR29c axis regulated glioma cell chemoresistance to TMZ through RNA mismatch repair pathway. XIST expression was up-regulated by miR29c inhibition while down-regulated by ectopic miR29, and XIST directly binds to miR29c to inhibit its expression, XIST and miR29c neatively regulates each other.

Key Molecule: hsa-mir-181 [81]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor.

Key Molecule: hsa-miR-198 [82]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: miR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT.

Key Molecule: hsa-mir-124 [83]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: M059k cells; Brain; Homo sapiens (Human); CVCL_0401
• In Vitro Model: U-87 MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 MG cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURkA. Re-expression of AURkA rescued miR124-mediated growth suppression.

Key Molecule: hsa-mir-203 [54]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: miR203-TS signaling pathway; Regulation; hsa05206
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR203 re-sensitizes TMZ resistant cells through directly targeting TS.

Key Molecule: Cancer susceptibility 2 (CASC2) [52]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN signaling pathway; Activation; hsa05235
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: LncRNA CASC2 interacts with miR181a to modulate glioma growth and resistance to TMZ through PTEN pathway.

Key Molecule: Cancer susceptibility 2 (CASC2) [52]

• Sensitive Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: CASC2 up-regulated PTEN protein and down-regulated p-AkT protein through regulating miR181a, and the effect of CASC2 on PTEN and p-AkT could be partially restored by miR181a.

Key Molecule: hsa-mir-181a [52]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN signaling pathway; Activation; hsa05235
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: CASC2 up-regulated PTEN protein and down-regulated p-AkT protein through regulating miR181a, and the effect of CASC2 on PTEN and p-AkT could be partially restored by miR181a.

Key Molecule: hsa-miR-433-3p [84]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Transwell migration assay; Annexin V/fluorescein isothiocyanate (FITC) apoptosis assay
• Mechanism Description: miR433-3p suppresses cell growth and enhances chemosensitivity by targeting CREB in human glioma, the overexpression of CREB can rescue the phenotype changes induced by miR433-3p overexpression.

Key Molecule: hsa-mir-101 [85]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: microRNA-101 reverses temozolomide resistance by inhibition of GSk3beta in glioblastoma.

Key Molecule: hsa-miR-370-3p [86]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: TMZ cytotoxicity assay; Colony formation assay; gamma -H2AX foci formation assay
• Mechanism Description: Up-regulation of miR370-3p restores glioblastoma multiforme sensitivity to temozolomide by influencing MGMT expression. MGMT was found to be inversely correlated with miR370-3p expression.

Key Molecule: hsa-mir-196b [87]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of miR-196b increased glioma cell sensitivity to TMZ and E2F1 decreased following transfection with miR-196b inhibitors.

Key Molecule: hsa-miR-7-5p [88]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7-5p suppresses stemness and enhances temozolomide sensitivity of drug-resistant glioblastoma cells by targeting Yin Yang 1.

Key Molecule: hsa-miR-181b-5p [89]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: Upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.

Key Molecule: hsa-mir-1271 [90]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The chemoresistant cell survival mediated with Bcl-2 was inhibited by overexpression of miR-1271 and was enhanced by depletion of miR-1271.

Key Molecule: hsa-miR-299-5p [91]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Inhibition of microRNA-299-5p sensitizes glioblastoma cells to temozolomide via upregulating GOLPH3 and inactivating the MAPk/ERk signaling pathway.

Key Molecule: hsa-miR-1268a [92]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1268a inhibited protein translation of ABCC1, which enhanced sensitivity of GBM cells to TMZ.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [62]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: hsa-mir-101 [62]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: hsa-mir-29c [93]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Ectopic expression of miR-29c increased TMZ sensitivity by inhibiting cell growth and promoting apoptosis in U251/TR cells.

Key Molecule: hsa-mir-10a [94]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Regulation; hsa04350
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA RP11-838N2.4 (+) TMZ sensitivity in GBM by serving as a ceRNA, sequestering with miR-10a on an epigenetic level.

Key Molecule: Long non-protein coding RNA (RP11-838N2.4) [94]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: TGF-beta signaling pathway; Regulation; hsa04350
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA RP11-838N2.4 (+) TMZ sensitivity in GBM by serving as a ceRNA, sequestering with miR-10a on an epigenetic level.

Key Molecule: hsa-mir-203 [95]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-203 was reversely associated with migration and invasion, and positively associated with chemosensitivity in glioma cells. E2F3 was shown to be a novel target of miR-203 and E2F3 knockdown exerted a similar effect to that of miR-203 overexpression. These results indicate that miR-203 may act as a tumor suppressor by targeting E2F3 in glioma cells and that miR-203/E2F3 may be a novel candidate for developing rational therapeutic strategies in glioma treatment.

Key Molecule: hsa-mir-128a [96]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Expression of Rap1B is negatively regulated by miR-128 and miR-149. TMZ inhibits Rap1B expression by upregulating miR-128 and miR-149. miR-128 and miR-149 suppress cell proliferation and invasion, and alter cytoskeletal remodeling by affecting Rap1B-associated small GTPase. miR-128 and miR-149 increase the chemosensitivity of TMZ in glioblastoma cells.

Key Molecule: hsa-mir-149 [96]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Expression of Rap1B is negatively regulated by miR-128 and miR-149. TMZ inhibits Rap1B expression by upregulating miR-128 and miR-149. miR-128 and miR-149 suppress cell proliferation and invasion, and alter cytoskeletal remodeling by affecting Rap1B-associated small GTPase. miR-128 and miR-149 increase the chemosensitivity of TMZ in glioblastoma cells.

Key Molecule: hsa-mir-125b [97]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: A novel mechanism independent of TP53 and MGMT by which oncogenic miR-125b confers TMZ resistance by targeting TNFAIP3 and NkIRAS2. GBM cells overexpressing miR-125b showed increased NF-kB activity and upregulation of anti-apoptotic and cell cycle genes. This was significantly associated with resistance of GBM cells to TNFalpha- and TNF-related inducing ligand-induced apoptosis as well as resistance to TMZ. Conversely, overexpression of anti-miR-125b resulted in cell cycle arrest, increased apoptosis and increased sensitivity to TMZ, indicating that endogenous miR-125b is sufficient to control these processes. GBM cells overexpressing TNFAIP3 and NkIRAS2 were refractory to miR-125b-induced apoptosis resistance as well as TMZ resistance, indicating that both genes are relevant targets of miR-125b.

Key Molecule: hsa-mir-181a [98]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ras-associated protein 1 (Rap1), a growth regulatory protein, belongs to a member of RAS-like small GTP-binding protein superfamily. Rap1 regulates several basic cellular functions: migration, adhesion and growth. TMZ can inhibit the Rap1B expression to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma.

Key Molecule: hsa-mir-181 [98]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ras-associated protein 1 (Rap1), a growth regulatory protein, belongs to a member of RAS-like small GTP-binding protein superfamily. Rap1 regulates several basic cellular functions: migration, adhesion and growth. TMZ can inhibit the Rap1B expression to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma.

Key Molecule: hsa-mir-181c [98]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ras-associated protein 1 (Rap1), a growth regulatory protein, belongs to a member of RAS-like small GTP-binding protein superfamily. Rap1 regulates several basic cellular functions: migration, adhesion and growth. TMZ can inhibit the Rap1B expression to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma.

Key Molecule: hsa-mir-181d [98]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ras-associated protein 1 (Rap1), a growth regulatory protein, belongs to a member of RAS-like small GTP-binding protein superfamily. Rap1 regulates several basic cellular functions: migration, adhesion and growth. TMZ can inhibit the Rap1B expression to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma.

Key Molecule: hsa-mir-125b [99]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: GSCs cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: Transwell invasion assay
• Mechanism Description: Inhibition of miR-125b expression may enhance sensitivity of GSCs to temozolomide by targeting PIAS3 on cell invasion.

Key Molecule: hsa-mir-17 [100]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U373-MG; Brain; Homo sapiens (Human); CVCL_2219
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: ATG7 is a potential target for miR-17, and this miRNA could negatively regulate ATG7 expression, resulting in a modulation of the autophagic status in T98G glioblastoma cells, the autophagy activation by anti-miR-17 resulted in a decrease of the threshold resistance at temozolomide doses in T98G cells.

Key Molecule: hsa-mir-181 [101]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-181b independently predicted chemoresponse to temozolomide and enhanced temozolomide sensitivity via MEk1 downregulation.

Key Molecule: hsa-miR-296-3p [38]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Key Molecule: hsa-mir-21 [102]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: D54MG cells; Brain; Homo sapiens (Human); CVCL_5735
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: TUNEL Analysis
• Mechanism Description: miR-21 is anti-apoptotic, and may promote glioma invasion and proliferation.

Key Molecule: hsa-mir-200c [103]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: Cell metastasis; Inhibition; hsa05205
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: DBTRG-05MG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-200c overexpression in DBTRG cells was able to downregulate both PDHA1 and TIGAR, which are involved in OXPHOS and glycolysis regulation. PDHA1 was described as the major provider of carbon for the TCA in GB. miR-200c overexpression was able to decrease DBTRG cell mobility. The observed effect of miR-200c on the mobility of DBTRG cells could be attributed to miR-200c modulation of E-cadherin levels, and consequent repression of epithelial-mesenchymal transition (EMT).

Key Molecule: hsa-mir-144 [104]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The increase of miR-144 levels, shown to be downregulated in U87 and DBTRG human GB cell lines, as well as in GB tumor samples, promoted the downregulation of mRNA of enzymes involved in bioenergetic pathways, with consequent alterations in cell metabolism, impairment of migratory capacity, and sensitization of DBTRG cells to a chemotherapeutic drug, the dichloroacetate (DCA).

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [92]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• Cell Pathway Regulation: Hedgehog signaling pathway; Inhibition; hsa04340
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• Cell Pathway Regulation: p53 signaling pathway; Inhibition; hsa04115
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; RIP assay; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Overexpression of miR-1268a inhibited protein translation of ABCC1, which enhanced sensitivity of GBM cells to TMZ.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [72]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: Glioblastoma tissue; .
• Experiment for Molecule Alteration: Real-time PCR
• Experiment for Drug Resistance: Patient survival time
• Mechanism Description: In the chemosensitive MDR1-negative parental cell line k562 10 ug/ml temozolomide resulted in pronounced cell death with only 47.1% surviving 48 h compared with the control. In contrast, in the highly MDR1-expressing resistant subline k562-VP16, cell death was significantly lower after exposure to temozolomide with 73.4% surviving 48 h (P = 0.002). Addition of a nontoxic dose of the MDR1-modulator cyclosporine A (1 uM) to temozolomide resulted in a trend towards restoration of chemosensitivity in the resistant MDR1-expressing cell line.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: hsa-mir-26b [105]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: SNB19 TR cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G TR cells; Brain; Homo sapiens (Human); CVCL_0556
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT Assay; Wound healing assay; Transwell invasion assays
• Mechanism Description: miR26b reverses temozolomide resistance via targeting Wee1 in glioma cells. miR26b governed TR-mediate EMT partly due to governing its target Wee1.

Key Molecule: Wee1-like protein kinase (WEE1) [105]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: SNB19 TR cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G TR cells; Brain; Homo sapiens (Human); CVCL_0556
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT Assay; Wound healing assay; Transwell invasion assays
• Mechanism Description: miR26b reverses temozolomide resistance via targeting Wee1 in glioma cells. miR26b governed TR-mediate EMT partly due to governing its target Wee1.

Key Molecule: Dynamin-3 (DNM3) [106]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vitro Model: HEB cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Transwell matrigel invasion assay; Scratch wound assay
• Mechanism Description: Exosomal miR221 targets DNM3 to induce tumor progression and temozolomide resistance in glioma. DNM3 is the target of miR221 and overexpression of DNM3 could reverse the miR221's tumour-promoting effect.

Key Molecule: hsa-mir-221 [106]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: SHG-44 cells; Brain; Homo sapiens (Human); CVCL_6728
• In Vitro Model: HEB cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Transwell matrigel invasion assay; Scratch wound assay
• Mechanism Description: Exosomal miR221 targets DNM3 to induce tumor progression and temozolomide resistance in glioma. DNM3 is the target of miR221 and overexpression of DNM3 could reverse the miR221's tumour-promoting effect.

Key Molecule: hsa-mir-143 [107]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: BALB/c nude mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; RT-PCR; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Matrigel assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-143 decreased glioma cell migration, invasion, tube formation and slowed tumor growth and angiogenesis in a manner associated with N-RAS downregulation in vitro and in vivo. miR-143 also sensitizes glioma cells to temozolomide (TMZ),the first-line drug for glioma treatment.

Key Molecule: hsa-mir-143 [107]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: BALB/c nude mice; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; RT-PCR; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Matrigel assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-143 decreased glioma cell migration, invasion, tube formation and slowed tumor growth and angiogenesis in a manner associated with N-RAS downregulation in vitro and in vivo. miR-143 also sensitizes glioma cells to temozolomide (TMZ),the first-line drug for glioma treatment.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcription factor SOX-2 (SOX2) [77]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; Flow cytometry assay
• Mechanism Description: miR-126-3p sensitizes glioblastoma cells to temozolomide by inactivating Wnt/beta-catenin signaling via targeting SOX2.

Key Molecule: High mobility group protein HMGI-C (HMGA2) [78]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U87 GSCs; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: miR-23b overexpression sensitized U87 glioma stem cells to TMZ-induced growth inhibition. And miR-23b had a synergistically suppressive effect on the expression of HMGA2 with TMZ in U87 GSCs.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [82], [86]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98 cells; Brain; Homo sapiens (Human); CVCL_B368
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay; TMZ cytotoxicity assay; gamma -H2AX foci formation assay
• Mechanism Description: miR-198 enhances temozolomide sensitivity in glioblastoma by targeting MGMT.

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [53]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U257 cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay; MTT assay; Transwell assay
• Mechanism Description: Upregulation of CASC2 sensitized glioma to temozolomide cytotoxicity through autophagy inhibition by sponging miR193a-5p and regulating mTOR expression. mTOR or CASC2 overexpression or miR193a-5p inhibition remarkably reduced autophagy-related proteins expression.

Key Molecule: TNF receptor-associated factor 6 (TRAF6) [80]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT/NF-kappaB signaling pathway; Inhibition; hsa05135
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR 146b 5p suppresses glioblastoma cell resistance to temozolomide through targeting TRAF6. Overexpression of miR 146b 5p or TRAF6 knockdown significantly decreased the level of p AkT and p p65.

Key Molecule: Epidermal growth factor receptor (EGFR) [81]

• Sensitive Disease: Glioblastoma multiforme [ICD-11: 2A00.03]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR181b modulates chemosensitivity of glioblastoma multiforme cells to temozolomide by targeting the epidermal growth factor receptor.

Key Molecule: Aurora kinase A (AURKA) [83]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: M059J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: M059k cells; Brain; Homo sapiens (Human); CVCL_0401
• In Vitro Model: U-87 MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 MG cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: U138-MG cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR124 suppresses glioblastoma growth and potentiates chemosensitivity by inhibiting AURkA. Re-expression of AURkA rescued miR124-mediated growth suppression.

Key Molecule: Thymidylate synthase (TYMS) [54]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis; Immunofluorescence assay
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: LncRNA MALAT1 inhibition re-sensitized TMZ resistant cells through up-regulating miR203 and down-regulating TS expression.

Key Molecule: Phosphatase and tensin homolog (PTEN) [52]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PTEN signaling pathway; Activation; hsa05235
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: CASC2 up-regulated PTEN protein and down-regulated p-AkT protein through regulating miR181a, and the effect of CASC2 on PTEN and p-AkT could be partially restored by miR181a.

Key Molecule: Phosphatase and tensin homolog (PTEN) [52]

• Sensitive Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; BrdU incorporation assay
• Mechanism Description: CASC2 up-regulated PTEN protein and down-regulated p-AkT protein through regulating miR181a, and the effect of CASC2 on PTEN and p-AkT could be partially restored by miR181a.

Key Molecule: Cyclic AMP-responsive element-binding protein 1 (CREB1) [84]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Transwell migration assay; Annexin V/fluorescein isothiocyanate (FITC) apoptosis assay
• Mechanism Description: miR433-3p suppresses cell growth and enhances chemosensitivity by targeting CREB in human glioma, the overexpression of CREB can rescue the phenotype changes induced by miR433-3p overexpression.

Key Molecule: Glycogen synthase kinase-3 beta (GSK3B) [85]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: microRNA-101 reverses temozolomide resistance by inhibition of GSk3beta in glioblastoma.

Key Molecule: Transcription factor E2F1 (E2F1) [87]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: Down-regulation of miR-196b increased glioma cell sensitivity to TMZ and E2F1 decreased following transfection with miR-196b inhibitors.

Key Molecule: Transcriptional repressor protein YY1 (TYY1) [88]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-7-5p suppresses stemness and enhances temozolomide sensitivity of drug-resistant glioblastoma cells by targeting Yin Yang 1.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [89]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay; Transwell assay
• Mechanism Description: Upregulation of miR-181b-5p targets Bcl-2 directly and may function as an important modifier to sensitize glioma cells to TMZ.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [90]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: The chemoresistant cell survival mediated with Bcl-2 was inhibited by overexpression of miR-1271 and was enhanced by depletion of miR-1271.

Key Molecule: Golgi phosphoprotein 3 (GOLPH3) [91]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell formation; Inhibition; hsa05200
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: MAPK/ERK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: LN308 cells; Brain; Homo sapiens (Human); CVCL_0394
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Inhibition of microRNA-299-5p sensitizes glioblastoma cells to temozolomide via upregulating GOLPH3 and inactivating the MAPk/ERk signaling pathway.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [62]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Methylation; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell colony; Inhibition; hsa05200
• Cell Pathway Regulation: Cell viability; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: The endogenous protein level of GSk3beta and MGMT was significantly suppressed by combination of MALAT1 knockdown and miR-101 overexpression and the promoter methylation of MGMT was largely promoted by the combination of MALAT1 knockdown and miR-101 overexpression.

Key Molecule: Transcription factor Sp1 (SP1) [93]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: DNA mismatch repair pathway; Regulation; hsa03430
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Ectopic expression of miR-29c increased TMZ sensitivity by inhibiting cell growth and promoting apoptosis in U251/TR cells.

Key Molecule: Transcription factor E2F3 (E2F3) [95]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U251-MG cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: miR-203 was reversely associated with migration and invasion, and positively associated with chemosensitivity in glioma cells. E2F3 was shown to be a novel target of miR-203 and E2F3 knockdown exerted a similar effect to that of miR-203 overexpression. These results indicate that miR-203 may act as a tumor suppressor by targeting E2F3 in glioma cells and that miR-203/E2F3 may be a novel candidate for developing rational therapeutic strategies in glioma treatment.

Key Molecule: Ras-related protein Rap-1b (RAP1B) [96]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Expression of Rap1B is negatively regulated by miR-128 and miR-149. TMZ inhibits Rap1B expression by upregulating miR-128 and miR-149. miR-128 and miR-149 suppress cell proliferation and invasion, and alter cytoskeletal remodeling by affecting Rap1B-associated small GTPase. miR-128 and miR-149 increase the chemosensitivity of TMZ in glioblastoma cells.

Key Molecule: NF-kappa-B inhibitor-interacting Ras-like protein 2 (NKIRAS2) [97]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: A novel mechanism independent of TP53 and MGMT by which oncogenic miR-125b confers TMZ resistance by targeting TNFAIP3 and NkIRAS2. GBM cells overexpressing miR-125b showed increased NF-kB activity and upregulation of anti-apoptotic and cell cycle genes. This was significantly associated with resistance of GBM cells to TNFalpha- and TNF-related inducing ligand-induced apoptosis as well as resistance to TMZ. Conversely, overexpression of anti-miR-125b resulted in cell cycle arrest, increased apoptosis and increased sensitivity to TMZ, indicating that endogenous miR-125b is sufficient to control these processes. GBM cells overexpressing TNFAIP3 and NkIRAS2 were refractory to miR-125b-induced apoptosis resistance as well as TMZ resistance, indicating that both genes are relevant targets of miR-125b.

Key Molecule: Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) [97]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: LN-18 cells; Brain; Homo sapiens (Human); CVCL_0392
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: A novel mechanism independent of TP53 and MGMT by which oncogenic miR-125b confers TMZ resistance by targeting TNFAIP3 and NkIRAS2. GBM cells overexpressing miR-125b showed increased NF-kB activity and upregulation of anti-apoptotic and cell cycle genes. This was significantly associated with resistance of GBM cells to TNFalpha- and TNF-related inducing ligand-induced apoptosis as well as resistance to TMZ. Conversely, overexpression of anti-miR-125b resulted in cell cycle arrest, increased apoptosis and increased sensitivity to TMZ, indicating that endogenous miR-125b is sufficient to control these processes. GBM cells overexpressing TNFAIP3 and NkIRAS2 were refractory to miR-125b-induced apoptosis resistance as well as TMZ resistance, indicating that both genes are relevant targets of miR-125b.

Key Molecule: Ras-related protein Rap-1b (RAP1B) [98]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Ras-associated protein 1 (Rap1), a growth regulatory protein, belongs to a member of RAS-like small GTP-binding protein superfamily. Rap1 regulates several basic cellular functions: migration, adhesion and growth. TMZ can inhibit the Rap1B expression to exert its cell killing by upregulating miR-181a/b/c/d subunits; conversely, each miR-181a/b/c/d subunit enhanced the chemosensitivity of TMZ in glioblastoma.

Key Molecule: E3 SUMO-protein ligase PIAS3 (PIAS3) [99]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: GSCs cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Transwell invasion assay
• Mechanism Description: Inhibition of miR-125b expression may enhance sensitivity of GSCs to temozolomide by targeting PIAS3 on cell invasion.

Key Molecule: Ubiquitin-like modifier-activating enzyme ATG7 (ATG7) [100]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell autophagy; Activation; hsa04140
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: U373-MG; Brain; Homo sapiens (Human); CVCL_2219
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Celltiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: ATG7 is a potential target for miR-17, and this miRNA could negatively regulate ATG7 expression, resulting in a modulation of the autophagic status in T98G glioblastoma cells, the autophagy activation by anti-miR-17 resulted in a decrease of the threshold resistance at temozolomide doses in T98G cells.

Key Molecule: MAPK/ERK kinase 1 (MEK1) [101]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-181b independently predicted chemoresponse to temozolomide and enhanced temozolomide sensitivity via MEk1 downregulation.

Key Molecule: Potassium voltage-gated channel subfamily H member 1 (KCNH1) [38]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Temozolomide
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U251AR cells; Brain; Homo sapiens (Human); CVCL_1G29
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: EAG1 channel might be involved in cell-cycle progression of tumour cells because a significant reduction in the proliferation of tumour cell lines could be achieved by inhibiting EAG1 expression using antisense oligonucleotides. Ectopic expression of miR-296-3p reduced EAG1 expression and suppressed cell proliferation drug resistance.

Teniposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-21 [108]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Teniposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: U373 MG cells; Brain; Homo sapiens (Human); CVCL_2219
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 likely contributes to VM-26 resistance through depression of the expression of LRRFIP1, leading to the reduction of the cytotoxicity of chemotherapy drugs through activation of the NF-kB pathway.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Leucine-rich repeat flightless-interacting protein 1 (LRRFIP1) [108]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Teniposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: U373 MG cells; Brain; Homo sapiens (Human); CVCL_2219
• Experiment for Molecule Alteration: Fluorescent reporter assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 likely contributes to VM-26 resistance through depression of the expression of LRRFIP1, leading to the reduction of the cytotoxicity of chemotherapy drugs through activation of the NF-kB pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181 [109]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Teniposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3'-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: E3 ubiquitin-protein ligase Mdm2 (MDM2) [109]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Teniposide
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: MDM2 is a candidate target of miR-181b. MDM2 knockdown mimicked the sensitization effect of miR-181b. Further study revealed that miR-181b binds to the 3'-UTR region of MDM2 leading to the decrease in MDM2 levels and subsequent increase in teniposide sensitivity. Partial restoration of MDM2 attenuated the sensitivity enhancement by miR-181b.

Tretinoin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Neurofibromin (NF1) [110], [111]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Alteration; .
• Resistant Drug: Tretinoin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK/RAS signaling pathway; Activation; hsa04010
• In Vitro Model: Kelly cells; Adrenal; Homo sapiens (Human); CVCL_2092
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: IMR-5 cells; Brain; Homo sapiens (Human); CVCL_1306
• In Vitro Model: NBL-S cells; Brain; Homo sapiens (Human); CVCL_2136
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: NF1 i.ctivation has been reported in neuroblastoma and confers activation of RAS-MAPk signalling and resistance to retinoic acid.

Vinblastine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [29]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vinblastine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Athymic nu/nu female mice xenograft model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold.

Vincristine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Glutathione S-transferase P (GSTP1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125b [31]

• Resistant Disease: Primitive neuroectodermal tumor [ICD-11: 2A00.08]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Resistant Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Anaplastic astrocytoma [ICD-11: 2A00.04]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Protein kinase C signaling pathways; Inhibition; hsa04310
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Oncotech EDR assay
• Mechanism Description: On the other hand, the frequency of LDR that we noted for paclitaxel (20%) and vincristine (20%) was similar to the clinical response rates for these compounds. These data suggest that although MDR1 expression by glial tumors may not be the dominant direct cellular process responsible for tumor resistance to natural products, other mechanisms are present that diminish their activity. The clinical mechanisms of natural product resistance may be a multifactorial function of endothelial expression of MDR1 at the blood-brain barrier in conjunction with glial tumor cell expression of alternative efflux pumps, such as MRP, altered tubulin with lower affinity binding sites, and/or protein kinase C signaling pathways that suppress apoptosis.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bcl-2 homologous antagonist/killer (BAK1) [31]

• Resistant Disease: Primitive neuroectodermal tumor [ICD-11: 2A00.08]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: miR125b-p53/BAKT signaling pathway; Activation; hsa05206
• In Vitro Model: RD-ES cells; Bones; Homo sapiens (Human); CVCL_2169
• In Vitro Model: Sk-ES cells; Bones; Homo sapiens (Human); CVCL_0627
• In Vitro Model: Sk-N-MC cells; Bones; Homo sapiens (Human); CVCL_0530
• In Vitro Model: TC-71 cells; Bones; Homo sapiens (Human); CVCL_2213
• In Vitro Model: VH-64 cells; Bones; Homo sapiens (Human); CVCL_9672
• In Vitro Model: WE-68 cells; Bones; Homo sapiens (Human); CVCL_9717
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Celltiter-glo luminescent cell viability assay
• Mechanism Description: miR-125b led to the development of chemoresistance by suppressing the expression of p53 and Bak, and repression of miR-125b sensitized EWS cells to apoptosis induced by treatment with various cytotoxic drugs.

Key Molecule: Methylated-DNA--protein-cysteine methyltransferase (MGMT) [6]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Vincristine
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Malignant gliomas tissue; .
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: EDR assay
• Mechanism Description: In vitro drug resistance in malignant gliomas was independent of prior therapy. High-grade glioblastomas showed a lower level of extreme drug resistance than low-grade astrocytomas to cisplatin (11% versus 27%), temozolomide (14% versus 27%), irinotecan (33% versus 53%), and BCNU (29% versus 38%). A substantial percentage of brain tumors overexpressed biomarkers associated with drug resistance, including MGMT (67%), GSTP1 (49%), and mutant p53 (41%). MGMT and GSTP1 overexpression was independently associated with in vitro resistance to BCNU, whereas coexpression of these two markers was associated with the greatest degree of BCNU resistance.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Sensitive Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Key Molecule: Multidrug resistance protein 1 (ABCB1) [37]

• Sensitive Disease: Ependymoma [ICD-11: 2A00.05]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• In Vitro Model: BXD-1425EPN cells; Embryo; Homo sapiens (Human); CVCL_Y105
• In Vitro Model: EPN1 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7 cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: EPN7R cells; Embryo; Homo sapiens (Human); N.A.
• In Vitro Model: DKFZ-EP1 cells; Embryo; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: ABCB1 gene expression was observed in 4 out of 5 paediatric ependymoma cell lines and increased in stem cell enriched neurospheres. Functional inhibition of ABCB1 using vardenafil or verapamil significantly (p < 0.05-0.001) potentiated the response to three chemotherapeutic drugs (vincristine, etoposide and methotrexate). Both inhibitors were also able to significantly reduce migration (p < 0.001) and invasion (p < 0.001).

Curcumin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-326 [112]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Curcumin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Inhibition; hsa05217
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR326 exerts a tumor inhibition effect by decreasing the activity of the SHH/GLI1 pathway. miR326 could target the SMO oncogene to inhibit the biological behaviors and stemness of glioma cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Smoothened homolog (SMO) [112]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Curcumin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: SHH/GLI1 signaling pathway; Inhibition; hsa05217
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR326 exerts a tumor inhibition effect by decreasing the activity of the SHH/GLI1 pathway. miR326 could target the SMO oncogene to inhibit the biological behaviors and stemness of glioma cells.

Dichloroacetate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-144 [104]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Dichloroacetate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The potential of miR-144 overexpression to reduce GB cell malignancy, both by decreasing Cell migration and invasion abilities and by sensitizing resistant tumor cells to chemotherapy, paving the way to a novel and more effective GB therapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [104]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dichloroacetate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The potential of miR-144 overexpression to reduce GB cell malignancy, both by decreasing Cell migration and invasion abilities and by sensitizing resistant tumor cells to chemotherapy, paving the way to a novel and more effective GB therapy.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [104]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dichloroacetate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The potential of miR-144 overexpression to reduce GB cell malignancy, both by decreasing Cell migration and invasion abilities and by sensitizing resistant tumor cells to chemotherapy, paving the way to a novel and more effective GB therapy.

Key Molecule: phosphoinositide-3-dependent protein kinase 1 (PDPK1) [104]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dichloroacetate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The potential of miR-144 overexpression to reduce GB cell malignancy, both by decreasing Cell migration and invasion abilities and by sensitizing resistant tumor cells to chemotherapy, paving the way to a novel and more effective GB therapy.

Key Molecule: Fructose-2,6-bisphosphatase TIGAR (TIGAR) [104]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Dichloroacetate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: Colorimetric SRB assay
• Mechanism Description: The potential of miR-144 overexpression to reduce GB cell malignancy, both by decreasing Cell migration and invasion abilities and by sensitizing resistant tumor cells to chemotherapy, paving the way to a novel and more effective GB therapy.

Clinical Trial Drug(s) 8 drug(s) in total

Capivasertib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: RAC-alpha serine/threonine-protein kinase (AKT1) [113]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.E17K (c.49G>A)
• Sensitive Drug: Capivasertib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The missense mutation p.E17K (c.49G>A) in gene AKT1 cause the sensitivity of Capivasertib by aberration of the drug's therapeutic target

Carboxyamidotriazole orotate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor/Protein Mdm4 (EGFR/MDM4) [114]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Structural mutation; Structural variation
• Resistant Drug: Carboxyamidotriazole orotate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Activation; hsa04151
• In Vivo Model: A retrospective survey in conducting clinical studies; Homo sapiens
• Experiment for Molecule Alteration: FISH assay; Whole-exome sequencing assay; Exome sequencing assay
• Experiment for Drug Resistance: Magnetic resonance imaging assay
• Mechanism Description: Indeed, EGFR and MDM4 FISH analysis of the patient-derived primary GBM cells from the second recurrence showed the presence of DMs, which are known to be resistant to targeted chemotherapies as previously reported.

Enasidenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [115]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.R172K (c.515G>A)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Key Molecule: Isocitrate dehydrogenase NADP 2 (IDH2) [115]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.R140Q (c.419G>A)
• Sensitive Drug: Enasidenib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87MG cells; Brain; Homo sapiens (Human); CVCL_GP63
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: TF-1a cells; Bone marrow; Homo sapiens (Human); CVCL_3608
• In Vitro Model: IDH2 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Mechanism Description: Somatic gain-of-function mutations in isocitrate dehydrogenases (IDH) 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite (R)-2-hydroxyglutarate (2HG). 2HG competitively inhibits alpha-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.

Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [116]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [116]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Selumetinib
• Experimental Note: Identified from the Human Clinical Data

Beta-lapachone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-218-2 [117]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Beta-lapachone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: HA-1800 cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay; Wound-healing analysis
• Mechanism Description: miR218-2 promotes glioblastomas growth, invasion and drug resistance by targeting CDC27, and the overexpression of CDC27 counteracted the function of miR218-2 in glioma cells. miR218-2 induces glioma malig.ncy by targeting CDC27, which leads to a decrease in the activation of the APC/C biquitin-proteosome pathway, probably downstream of the TGFbeta signaling pathways.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cell division cycle protein 27 homolog (CDC27) [117]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Beta-lapachone
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: U118 cells; Brain; Homo sapiens (Human); CVCL_0633
• In Vitro Model: HA-1800 cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis; Immunohistochemistry (IHC) assay
• Experiment for Drug Resistance: CCK8 assay; Soft agar colony formation assay; Wound-healing analysis
• Mechanism Description: miR218-2 promotes glioblastomas growth, invasion and drug resistance by targeting CDC27, and the overexpression of CDC27 counteracted the function of miR218-2 in glioma cells. miR218-2 induces glioma malig.ncy by targeting CDC27, which leads to a decrease in the activation of the APC/C biquitin-proteosome pathway, probably downstream of the TGFbeta signaling pathways.

Patidegib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Smoothened homolog (SMO) [118]

• Sensitive Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Missense mutation; p.D473H (c.1417G>C)
• Sensitive Drug: Patidegib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Bone marrow; .
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.D473H (c.1417G>C) in gene SMO cause the sensitivity of Patidegib by unusual activation of pro-survival pathway

Ulixertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [119]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Ulixertinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MAPK signaling pathway; Inhibition; hsa04010

PLX4720

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [120]

• Resistant Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Resistant Drug: PLX4720
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar blue proliferation assay

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [121]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: PLX4720
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U138 cells; Brain; Homo sapiens (Human); CVCL_0020
• In Vitro Model: T98G cells; Brain; Homo sapiens (Human); CVCL_0556
• In Vitro Model: HS683 cells; Brain; Homo sapiens (Human); CVCL_0844
• In Vitro Model: DBTRG-05MG cells; Brain; Homo sapiens (Human); CVCL_1169
• In Vitro Model: NMC-G1 cells; Brain; Homo sapiens (Human); CVCL_1608
• In Vitro Model: MO59J cells; Brain; Homo sapiens (Human); CVCL_0400
• In Vitro Model: LN405 cells; Brain; Homo sapiens (Human); CVCL_1378
• In Vitro Model: LN172 cells; N.A.; .; N.A.
• In Vitro Model: KG1c cells; Brain; Homo sapiens (Human); CVCL_2971
• In Vitro Model: H4 cells; Brain; Homo sapiens (Human); CVCL_1239
• In Vitro Model: GMS10 cells; Brain; Homo sapiens (Human); CVCL_1233
• In Vitro Model: GAMG cells; Brain; Homo sapiens (Human); CVCL_1226
• In Vitro Model: CCF-STTG1 cells; Brain; Homo sapiens (Human); CVCL_1118
• In Vitro Model: AM-38 cells; Brain; Homo sapiens (Human); CVCL_1070
• In Vitro Model: 8MGBA cells; Brain; Homo sapiens (Human); CVCL_1052
• In Vitro Model: 42MGBA cells; Brain; Homo sapiens (Human); CVCL_1798
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay
• Mechanism Description: PLX4720 suppresses MEK-ERK phosphorylation and cell proliferation in MA cells containing BRAFV600E mutation.

Discontinued Drug(s) 1 drug(s) in total

Cevipabulin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 1 (ABCB1) [29]

• Resistant Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cevipabulin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Athymic nu/nu female mice xenograft model; Mus musculus
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The compound was a weak substrate of multidrug resistance 1 (multidrug resistance transporter or P-glycoprotein). In a cell line expressing a high level of P-glycoprotein, the IC50 of TTI-237 increased 25-fold whereas those of paclitaxel and vincristine increased 806-fold and 925-fold, respectively.

Preclinical Drug(s) 11 drug(s) in total

AGI-5198

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [122]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: AGI-5198
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [122]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132C (c.394C>T)
• Sensitive Drug: AGI-5198
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132C (c.394C>T) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [122]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: AGI-5198
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of AGI-5198 by aberration of the drug's therapeutic target

AZD3463/Doxorubicin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: ALK tyrosine kinase receptor (ALK) [123]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.D1091N (c.3271G>A)
• Sensitive Drug: AZD3463/Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K signaling pathway; Inhibition; hsa04151
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: LA-N-6 cells; Bone marrow; Homo sapiens (Human); CVCL_1363
• In Vivo Model: Athymic NCR nude mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay; FACS assay; Propidium iodide staining assay; MTT assay
• Mechanism Description: The novel ALK inhibitor alectinib effectively suppressed cell proliferation and induces apoptosis in NB cell lines with either wild-type ALK or mutated ALK (F1174L and D1091N) by blocking ALK-mediated PI3K/Akt/mTOR signaling. In addition, alectinib enhanced doxorubicin-induced cytotoxicity and apoptosis in NB cells. Furthermore, alectinib induced apoptosis in an orthotopic xenograft NB mouse model. Also, in the TH-MYCN transgenic mouse model, alectinib resulted in decreased tumor growth and prolonged survival time.

BI-2536

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [120]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: BI-2536
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Athymic mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Alamar blue proliferation assay

BPTES

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [124]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: BPTES
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: 3H-thymidine incorporation assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of BPTES by unusual activation of pro-survival pathway

Everolimus/Binimetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Nras (NRAS) [125]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.Q61K (c.181C>A)
• Sensitive Drug: Everolimus/Binimetinib
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/mTOR signaling pathway; Inhibition; hsa04151
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: NGP cells; Lung; Homo sapiens (Human); CVCL_2141
• In Vitro Model: CHP-212 cells; Brain; Homo sapiens (Human); CVCL_1125
• In Vitro Model: CHP-134 cells; Adrenal gland; Homo sapiens (Human); CVCL_1124
• Experiment for Molecule Alteration: Western blotting analysis; PCR
• Experiment for Drug Resistance: Promega assay; FACS assay
• Mechanism Description: Combination of mTOR and MEK inhibitors synergistically inhibit downstream signaling and cell growth of NRAS mutant cell lines.

Everolimus/PLX4720

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [126]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Everolimus/PLX4720
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• In Vitro Model: SF9427 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SF8628 cells; Brain; Homo sapiens (Human); CVCL_IT46
• In Vitro Model: SF188 cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: BT40 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: AM-38 cells; Brain; Homo sapiens (Human); CVCL_1070
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Combination therapy in BRAFV600E-mutant human glioma cells enhances cell cycle arrest and apoptosis and reduces proliferation compared to monotherapy.

Everolimus/Selumetinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [126]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Everolimus/Selumetinib
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BRAF/MEK/MAPK signaling pathway; Inhibition; hsa04010
• In Vitro Model: DBTRG cells; Brain; Homo sapiens (Human); CVCL_1169
• In Vitro Model: SF9427 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: SF8628 cells; Brain; Homo sapiens (Human); CVCL_IT46
• In Vitro Model: SF188 cells; Brain; Homo sapiens (Human); CVCL_6948
• In Vitro Model: BT40 cells; N.A.; Homo sapiens (Human); N.A.
• In Vitro Model: AM-38 cells; Brain; Homo sapiens (Human); CVCL_1070
• In Vivo Model: NSG mouse PDX model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: Combination therapy in BRAFV600E-mutant human glioma cells enhances cell cycle arrest and apoptosis and reduces proliferation compared to monotherapy.

hEGFR vIII-CD3 bi-scFv

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [127]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Complex-indel; (c.89_889del11867)
• Sensitive Drug: hEGFR vIII-CD3 bi-scFv
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U87-MG cells; Brain; Homo sapiens (Human); CVCL_0022
• Experiment for Drug Resistance: Chromium release assay; FACS assay

IDH1 inhibitors

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [122]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: IDH1 inhibitors
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TS676 cells; Brain; Homo sapiens (Human); CVCL_A5HX
• In Vitro Model: TS603 cells; Brain; Homo sapiens (Human); CVCL_A5HW
• In Vitro Model: TS516 cells; Brain; Homo sapiens (Human); CVCL_A5HY
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Soft agar assay
• Mechanism Description: The missense mutation p.R132H (c.395G>A) in gene IDH1 cause the sensitivity of IDH1 inhibitors by aberration of the drug's therapeutic target

SF1126

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: GTPase Hras (HRAS) [128]

• Sensitive Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Missense mutation; p.G12V (c.35G>T)
• Sensitive Drug: SF1126
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: U87MG glioma cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Athymic female (CD-1 Nu/Nu) mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Kinase-Glo luminescent assay

YM-024

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PI3-kinase alpha (PIK3CA) [129]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.H1047Y (c.3139C>T)
• Sensitive Drug: YM-024
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: SK-MG-26 cell; N.A.; Homo sapiens (Human); CVCL_D701
• In Vitro Model: SK-MG-17 cells; N.A.; Homo sapiens (Human); CVCL_8574
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter96 AQueous assay; Soft-agar colony formation assay

Investigative Drug(s) 15 drug(s) in total

2-hydroxy-5-fluoropyrimidine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: L1 cell adhesion molecule (L1CAM) [2]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: 2-hydroxy-5-fluoropyrimidine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• In Vitro Model: MDCK cells; Kidney; Canis lupus familiaris (Dog) (Canis familiaris); CVCL_0422
• Experiment for Molecule Alteration: Puromycin selection and monitored regularly for the maintenance of L1 silencing assay
• Experiment for Drug Resistance: Migration assay
• Mechanism Description: With OVCAR3 cells treated with anagrelide, 2-hydroxy-5-fluoropyrimidine and mestranol , the gap width closure was seen from 48 h onward at all concentrations tested. Similar results were obtained with U251 cells, and L1's metastatic potential is further evidenced by its promotion of epithelial-mesenchymal transition, endothelial cell transcytosis and resistance to chemo- and radiotherapy.

Apigenin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-423-5p [130]

• Sensitive Disease: Glioma [ICD-11: 2A00.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Apigenin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Bax/BCL2/caspase-3 signaling pathway; Activation; hsa04933
• Cell Pathway Regulation: Mitochondrial signaling pathway; Regulation; hsa04217
• In Vitro Model: CD133-positive cells; Brain; Homo sapiens (Human); CVCL_IR55
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Annexin V/PI apoptosis assay; Caspase-3 activity assay
• Mechanism Description: Retracted-miR423-5p knockdown enhances the sensitivity of glioma stem cells to apigenin through the mitochondrial pathway.

AZD3463

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: ALK tyrosine kinase receptor (ALK) [131]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L (c.3520T>C)
• Sensitive Drug: AZD3463
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: NGP cells; Lung; Homo sapiens (Human); CVCL_2141
• In Vitro Model: N b-19 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Orthotopic Mouse Model of NB; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay; Colony formation assay

Key Molecule: ALK tyrosine kinase receptor (ALK) [131]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L (c.3522C>A)
• Sensitive Drug: AZD3463
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: IMR-32 cells; Abdomen; Homo sapiens (Human); CVCL_0346
• In Vitro Model: Sk-N-AS cells; Adrenal; Homo sapiens (Human); CVCL_1700
• In Vitro Model: SH-SY5Y cells; Abdomen; Homo sapiens (Human); CVCL_0019
• In Vitro Model: NGP cells; Lung; Homo sapiens (Human); CVCL_2141
• In Vitro Model: N b-19 cells; N.A.; Homo sapiens (Human); N.A.
• In Vivo Model: Orthotopic Mouse Model of NB; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay; Colony formation assay

CEP-28122

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [132]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L (c.3520T>C)
• Sensitive Drug: CEP-28122
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.F1174L (c.3520T>C) in gene ALK cause the sensitivity of CEP-28122 by aberration of the drug's therapeutic target

Key Molecule: ALK tyrosine kinase receptor (ALK) [132]

• Sensitive Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.R1275Q (c.3824G>A)
• Sensitive Drug: CEP-28122
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SUP-M2 cells; Colon; Homo sapiens (Human); CVCL_2209
• In Vitro Model: KARPAS-299 cells; Peripheral blood; Homo sapiens (Human); CVCL_1324
• In Vivo Model: mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The missense mutation p.R1275Q (c.3824G>A) in gene ALK cause the sensitivity of CEP-28122 by aberration of the drug's therapeutic target

Cisplatinum

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOXD antisense growth-associated long non-coding RNA (HAGLR) [10]

• Resistant Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: Cisplatinum
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: SNB19 cells; Brain; Homo sapiens (Human); CVCL_0535
• In Vitro Model: U373 cells; Brain; Homo sapiens (Human); CVCL_2219
• In Vitro Model: NHA cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: BALB/c nude mice model; Mus musculus
• Experiment for Molecule Alteration: Knockdown assay; Overexpression assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Knockdown of LncRNA HOXD-AS1 suppresses proliferation, migration and invasion and enhances cisplatin sensitivity of glioma cells by sponging miR-204.

Cobimetinib/Vemurafenib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [133]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Cobimetinib/Vemurafenib
• Experimental Note: Identified from the Human Clinical Data

EGFR TKIs

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Epidermal growth factor receptor (EGFR) [134]

• Resistant Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: IF-deletion; p.V30_V336 (c.88_1008)
• Resistant Drug: EGFR TKIs
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Mechanism Description: The if-deletion p.V30_V336 (c.88_1008) in gene EGFR cause the resistance of EGFR TKIs by aberration of the drug's therapeutic target.

Key Molecule: Epidermal growth factor receptor (EGFR) [135]

• Resistant Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Copy number gain; .
• Resistant Drug: EGFR TKIs
• Experimental Note: Identified from the Human Clinical Data

FGFR inhibitors

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor (FGFR) [136]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Chromosomal translocations; FGFR-TACC gene fusions
• Resistant Drug: FGFR inhibitors
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Screening assay
• Mechanism Description: In particular, epidermal growth factor receptor (EGFR) activation has been identified as a mechanism of resistance in bladder cancer cells with FGFR3 mutations after treatment with FGFR inhibitors.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hepatocyte growth factor receptor (MET) [136]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Mutation; .
• Resistant Drug: FGFR inhibitors
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK/MAPKsignaling pathway; Activation; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• Cell Pathway Regulation: STAT3 signaling pathway; Activation; hsa04550
• Experiment for Molecule Alteration: Sanger sequencing assay
• Experiment for Drug Resistance: Screening assay
• Mechanism Description: In particular, epidermal growth factor receptor (EGFR) activation has been identified as a mechanism of resistance in bladder cancer cells with FGFR3 mutations after treatment with FGFR inhibitors.

GDP-beta-L-galactose

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Smoothened homolog (SMO) [137]

• Resistant Disease: Medulloblastoma [ICD-11: 2A00.10]
• Molecule Alteration: Missense mutation; p.D473H
• Resistant Drug: GDP-beta-L-galactose
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Hedgehog signaling pathway; Activation; hsa04340
• Experiment for Molecule Alteration: Deep sequencing assay
• Experiment for Drug Resistance: Fluorescence-activated cell sorting (FACS) analysis
• Mechanism Description: Molecular profiling of the medulloblastoma patient's primary and metastatic tumor taken before treatment with GDC-0449 revealed an underlying somatic mutation in PTCH1 (PTCH1-W844C) as well as up-regulated expression of Hh pathway target genes, supporting the hypothesis that the tumor was driven by dysregulated Hh signaling. SMO-D473H transfection induced Hh pathway activity to levels comparable with that seen with SMO-WT, demonstrating that SMO-D473H is fully capable of activating Hh signaling.

I-BET151

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [138]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: I-BET151
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U87Luc cells; Brain; Homo sapiens (Human); CVCL_5J12
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Colony forming assay; Flow cytometry assay
• Mechanism Description: The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation to promote I-bet151 resistance in Glioblastoma.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Bromodomain-containing protein 4 (BRD4) [138]

• Resistant Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: I-BET151
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: U87Luc cells; Brain; Homo sapiens (Human); CVCL_5J12
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Colony forming assay; Flow cytometry assay
• Mechanism Description: The Bromodomain protein BRD4 controls HOTAIR, a long noncoding RNA essential for glioblastoma proliferation to promote I-bet151 resistance in Glioblastoma.

Isoarnebin 4

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-143 [139]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Isoarnebin 4
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-143 enhances the antitumor activity of shikonin by targeting BAG3 and reducing its expression in human glioblastoma stem cell.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: BAG family molecular chaperone regulator 3 (BAG3) [139]

• Sensitive Disease: Glioblastoma [ICD-11: 2A00.02]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Isoarnebin 4
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Mitochondrial apoptotic signaling pathway; Activation; hsa04210
• In Vitro Model: GBM cells; Brain; Homo sapiens (Human); N.A.
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-143 enhances the antitumor activity of shikonin by targeting BAG3 and reducing its expression in human glioblastoma stem cell.

Isoliquiritigenin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Nuclear paraspeckle assembly transcript 1 (NEAT1) [140]

• Resistant Disease: Brain glioma [ICD-11: 2A00.0]
• Molecule Alteration: Down-regulation; Interaction
• Resistant Drug: Isoliquiritigenin
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: C6 cells; Brain; Rattus norvegicus (Rat); CVCL_0194
• Experiment for Molecule Alteration: qRT-PCR; Western bloting analysis; Immunofluorescence assay; ELISA assay; Luciferase assay; Overexpression assay
• Mechanism Description: LncRNA NEAT1 overexpression reversed ISL-mediated increase in miR-194-5p expression, and thereby attenuated FGF-2, TGF-beta and VEGF production.

NSC141562

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-155 [141]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: NSC141562
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Wound healing assay; Transwell assay; MTT assay
• Mechanism Description: miR155HG Is a Mesenchymal Transition-Associated Long Noncoding RNA, miR155-5p and miR155-3p Are key Derivatives of MIR155HG. miR155-5p or miR155-3p Targets Protocadherin 9 or 7, Respectively, Protocadherin 9 and 7 Function as Tumor Suppressor Genes by Inhibiting the Wnt/ beta-catenin signaling pathway.

Key Molecule: MIR155 host gene (MIR155HG) [141]

• Resistant Disease: Malignant glioma [ICD-11: 2A00.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: NSC141562
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Activation; hsa01521
• Cell Pathway Regulation: Wnt/beta-catenin signaling pathway; Activation; hsa04310
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR; Microarray assay
• Experiment for Drug Resistance: CCK8 assay; Wound healing assay; Transwell assay; MTT assay
• Mechanism Description: miR155HG Is a Mesenchymal Transition-Associated Long Noncoding RNA, miR155-5p and miR155-3p Are key Derivatives of MIR155HG. miR155-5p or miR155-3p Targets Protocadherin 9 or 7, Respectively, Protocadherin 9 and 7 Function as Tumor Suppressor Genes by Inhibiting the Wnt/ beta-catenin signaling pathway.

NVP-TAE684

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: ALK tyrosine kinase receptor (ALK) [1]

• Resistant Disease: Neuroblastoma [ICD-11: 2A00.11]
• Molecule Alteration: Missense mutation; p.F1174L
• Resistant Drug: NVP-TAE684
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: NBLW cells; Brain; Homo sapiens (Human); CVCL_VJ90
• In Vitro Model: NBLW-R cells; Brain; Homo sapiens (Human); CVCL_VJ91
• Experiment for Molecule Alteration: Sangersequencing assay; Targeted deep sequencing assay
• Experiment for Drug Resistance: Array CGH assay
• Mechanism Description: Analysis of the sensitivity of NBLW and NBLW-R cells to a panel of ALk inhibitors (TAE-684, Crizotinib, Alectinib and Lorlatinib) revealed differences between the paired cell lines, and overall NBLW-R cells with the F1174L mutation were more resistant to ALk inhibitor induced apoptosis compared with NBLW cells.

Temozolomide/Vandetanib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [142]

• Sensitive Disease: FGFR-tacc positive glioblastoma [ICD-11: 2A00.01]
• Molecule Alteration: Missense mutation; p.R132H (c.395G>A)
• Sensitive Drug: Temozolomide/Vandetanib
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Brain; .
• Experiment for Molecule Alteration: Multiplex array; Standard ELISA assay
• Experiment for Drug Resistance: Pharmacokinetics analysis

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