Disease Information

General Information of the Disease (ID: DIS00072)

• Name: Colon cancer
• ICD: ICD-11: 2B90

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) 18 drug(s) in total

Bortezomib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-101 [1]

• Sensitive Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Bortezomib
• 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: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Proteasome maturation protein (POMP) [1]

• Sensitive Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Bortezomib
• 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: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-101 functions as an endogenous proteasome inhibitor by targeting POMP. Targeting POMP is essential for cell growth suppression by miR-101. High miR-101 levels have good outcomes for ERalpha-positive breast cancer patients. Targeting POMP inhibits tumor progression and overcomes resistance to bortezomib.

Calcitriol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: H19, imprinted maternally expressed transcript (H19) [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Calcitriol
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: H19 overexpression induces resistance to 1,25(OH)2D3 by inhibiting the expression of VDR Through miR675-5p in colon cancer cells. vdr signaling was able to attenuate the proliferation and migration of colon cancer cells via multiple mechanisms including inhibiting Wnt/beta-catenin pathway, VDR signaling inhibits the expression of h19 by regulating the C-Myc/mad-1 Network.

Key Molecule: hsa-miR-675-5p [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Calcitriol
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: H19 overexpression induces resistance to 1,25(OH)2D3 by inhibiting the expression of VDR Through miR675-5p in colon cancer cells. vdr signaling was able to attenuate the proliferation and migration of colon cancer cells via multiple mechanisms including inhibiting Wnt/beta-catenin pathway, VDR signaling inhibits the expression of h19 by regulating the C-Myc/mad-1 Network.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Vitamin D3 receptor (VDR) [2]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Calcitriol
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: H19 overexpression induces resistance to 1,25(OH)2D3 by inhibiting the expression of VDR Through miR675-5p in colon cancer cells. vdr signaling was able to attenuate the proliferation and migration of colon cancer cells via multiple mechanisms including inhibiting Wnt/beta-catenin pathway, VDR signaling inhibits the expression of h19 by regulating the C-Myc/mad-1 Network.

Capecitabine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-296 [3]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Capecitabine
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: The patients with decrease in miR-296 at 4 weeks may reflect a more aggressive tumor phenotype with increased metastasis and tumor cell invasiveness. The loss of miR-296 may be one of the mechanisms for primary resistance of colorectal cancer to chemotherapy.

Cetuximab

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-199a-5p [4]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GEO CR cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AkT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Key Molecule: hsa-mir-375 [4]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GEO CR cells; Colon; Homo sapiens (Human); CVCL_0271
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AkT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: PH domain leucine-rich repeat-containing protein phosphatase 1 (PHLPP1) [4]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cetuximab
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT signaling pathway; Inhibition; hsa04151
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: GEO CR cells; Colon; Homo sapiens (Human); CVCL_0271
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The ability of miR-199a-5p and miR-375 to target PHLPP1 (PH domain and leucine-rich repeat protein phosphatase 1), a tumor suppressor that negatively regulates the AkT pathway, accounts, at least in part, for their drug-resistance activity. Indeed, restoration of PHLPP1 increases sensitivity of the GEO cells to CTX and reverts the resistance-promoting effect of miR-199a-5p and miR-375.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-143 [5]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cetuximab
• 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
• Cell Pathway Regulation: EGFR/RAS/MAPK signaling pathway; Regulation; hsa01521
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The extent of caspase and nuclear fragmentation inhibition was higher in cells overexpressing miR-143 or miR-145, which also display reduced Bcl-2 protein steady-state levels. restoration of miR-143 or miR-145 reduces the aggressiveness of mutant kRAS HCT116 cells. In addition, forced expression of these miRNAs in both mutant and wild-type kRAS colon cancer cells increased their sensitivity to cetuximab by increasing cetuximab-mediated ADCC. Moreover, increased levels of effector cell-mediated caspase-dependent apoptosis were observed for mutant kRAS HCT116 miRNAs-overexpressing cells.

Key Molecule: hsa-mir-145 [5]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cetuximab
• 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
• Cell Pathway Regulation: EGFR/RAS/MAPK signaling pathway; Regulation; hsa01521
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Northern blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The extent of caspase and nuclear fragmentation inhibition was higher in cells overexpressing miR-143 or miR-145, which also display reduced Bcl-2 protein steady-state levels. restoration of miR-143 or miR-145 reduces the aggressiveness of mutant kRAS HCT116 cells. In addition, forced expression of these miRNAs in both mutant and wild-type kRAS colon cancer cells increased their sensitivity to cetuximab by increasing cetuximab-mediated ADCC. Moreover, increased levels of effector cell-mediated caspase-dependent apoptosis were observed for mutant kRAS HCT116 miRNAs-overexpressing cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [5]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cetuximab
• 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
• Cell Pathway Regulation: EGFR/RAS/MAPK signaling pathway; Regulation; hsa01521
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: The extent of caspase and nuclear fragmentation inhibition was higher in cells overexpressing miR-143 or miR-145, which also display reduced Bcl-2 protein steady-state levels. restoration of miR-143 or miR-145 reduces the aggressiveness of mutant kRAS HCT116 cells. In addition, forced expression of these miRNAs in both mutant and wild-type kRAS colon cancer cells increased their sensitivity to cetuximab by increasing cetuximab-mediated ADCC. Moreover, increased levels of effector cell-mediated caspase-dependent apoptosis were observed for mutant kRAS HCT116 miRNAs-overexpressing cells.

Chloroquinine phosphate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: tumor protein p53 pathway corepressor 1 (TP53COR1) [6]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Up-regulation; Interaction
• Resistant Drug: Chloroquinine phosphate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR; Western bloting analysis; Immunoprecipitation; Knockdown assay
• Mechanism Description: LincRNA-p21 Mediates the Anti-Cancer Effect of Ginkgo Biloba Extract EGb 761 by Stabilizing E-Cadherin Protein in Colon Cancer.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-155 [7]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vivo Model: miR-155 knockout mouse model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTS assay; Caspase 3 activity assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-155 was associated with decreased levels of FOXO3, primarily through inhibiting the expression of FOXO3 to increase colon cancer resistanec to cisplatin.

Key Molecule: hsa-mir-155 [8]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• 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: NF-kappaB signaling pathway; Activation; hsa04064
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Adrenaline increased miR-155 expression in an NFkB dependent manner. HT29 cells overexpressing miR-155 had a higher cell growth rate and more resistance to cisplatin induced apoptosis. In contrast, HT29 cells overexpressing miR-155 inhibitor displayed decreased cell proliferation and sensitivity to cisplatin induced cell death. In summary, our study here revealed that adrenaline-NFkB-miR-155 pathway at least partially contributes to the psychological stress induced proliferation and chemoresistance in HT29 cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [7]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vivo Model: miR-155 knockout mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Caspase 3 activity assay; Flow cytometry assay
• Mechanism Description: Overexpression of miR-155 was associated with decreased levels of FOXO3, primarily through inhibiting the expression of FOXO3 to increase colon cancer resistanec to cisplatin.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Long non-protein coding RNA 261 (LINC00261) [9]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell metastasis; Activation; hsa05205
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LINC00261 down-regulated beta-catenin in nuclei and promoted beta-catenin degradation, i.ctivated Wnt/beta-catenin pathway and downstream target genes, then inhibited TCF/LEF/beta-catenin complex formation, and finally, repressed colon cancer and reduced the cisplatin resistance of tumor cells.

Key Molecule: hsa-mir-101 [10]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; AO/EB double staining; Transwell invasion assay
• Mechanism Description: Upregulation of miR101 enhances the cytotoxic effect of anticancer drugs through inhibition of colon cancer cell proliferation. The upregulated expression of miR101 inhibited proliferation and migration, and increased the sensitivity of colon cancer cells to chemotherapy.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [9]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Cisplatin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: Cell metastasis; Inhibition; hsa05205
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LINC00261 down-regulated beta-catenin in nuclei and promoted beta-catenin degradation, i.ctivated Wnt/beta-catenin pathway and downstream target genes, then inhibited TCF/LEF/beta-catenin complex formation, and finally, repressed colon cancer and reduced the cisplatin resistance of tumor cells.

Cyclophosphamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Drug Inactivation by Structure Modification (DISM)

Key Molecule: Cytochrome P450 family 3 subfamily A member1 (CYP3A4) [11]

• Resistant Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Cyclophosphamide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LS-180 cells; Colon; Homo sapiens (Human); CVCL_0397
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Sulforhodamine B assay
• Mechanism Description: CYP3A4 is the most abundant hepatic and intestinal cytochrome P450 enzyme in humans, contributing to the metabolism of various drugs such as benzodiazepines, HIV antivirals, macrolide antibiotics, and statins. CYP3A4 3'UTR-luciferase activity was significantly decreased in human embryonic kidney 293 cells transfected with plasmid that expressed microRNA-27b (miR-27b) or mouse microRNA-298 (mmu-miR-298), overexpression of miR-27b or mmu-miR-298 in PANC1 cells led to a lower sensitivity to cyclophosphamide.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-27b [11]

• Resistant Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Cyclophosphamide
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LS-180 cells; Colon; Homo sapiens (Human); CVCL_0397
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Sulforhodamine B assay
• Mechanism Description: CYP3A4 is the most abundant hepatic and intestinal cytochrome P450 enzyme in humans, contributing to the metabolism of various drugs such as benzodiazepines, HIV antivirals, macrolide antibiotics, and statins. CYP3A4 3'UTR-luciferase activity was significantly decreased in human embryonic kidney 293 cells transfected with plasmid that expressed microRNA-27b (miR-27b) or mouse microRNA-298 (mmu-miR-298), overexpression of miR-27b or mmu-miR-298 in PANC1 cells led to a lower sensitivity to cyclophosphamide.

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-424 [12]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• 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 proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [12]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• 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 proliferation; Activation; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-522 [13]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: When miR 522 was overexpressed in the HT29/DOX cells, the protein expression levels of ABCB5 were downregulated. Furthermore, knockdown of ABCB5 significantly increased the growth inhibition rate of the HT29/DOX cells, compared with the control group. These results suggested that miR 522 may affect the sensitivity of colon cancer cell lines to DOX treatment by targeting ABCB5.

Key Molecule: hsa-mir-137 [14]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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: LS174 cells; Colon; Homo sapiens (Human); CVCL_YJ85
• 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.

Key Molecule: hsa-mir-195 [15]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Suppression of miR-195 leads to elevation of its direct target gene BCL2L2 expression therefore makes the human colon cancer cells more resistant to Dox.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [13]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• 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: When miR 522 was overexpressed in the HT29/DOX cells, the protein expression levels of ABCB5 were downregulated. Furthermore, knockdown of ABCB5 significantly increased the growth inhibition rate of the HT29/DOX cells, compared with the control group. These results suggested that miR 522 may affect the sensitivity of colon cancer cell lines to DOX treatment by targeting ABCB5.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Nuclear receptor subfamily 1 group I3 (NR1I3) [14]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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: LS174 cells; Colon; Homo sapiens (Human); CVCL_YJ85
• 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: Bcl-2-like protein 2 (BCL2L2) [15]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Doxorubicin
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Suppression of miR-195 leads to elevation of its direct target gene BCL2L2 expression therefore makes the human colon cancer cells more resistant to Dox.

Etoposide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-424 [12]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Etoposide
• 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: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Programmed cell death protein 4 (PDCD4) [12]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Etoposide
• 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: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vitro Model: PARP cells; Skin; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Hypoxia induces miR-424 expression and that miR-424 in turn suppresses the level of PDCD4 protein, a tumor suppressor that is involved in apoptosis, by targeting its 3' untranslated region. Functionally, miR-424 overexpression decreases the sensitivity of cancer cells (HCT116 and A375) to doxorubicin (Dox) and etoposide. In contrast, the inhibition of miR-424 (+) apoptosis and increased the sensitivity of cancer cells to Dox. In a xenograft tumor model, miR-424 overexpression promoted tumor growth following Dox treatment, suggesting that miR-424 promotes tumor cell resistance to Dox. Furthermore, miR-424 levels are inversely correlated with PDCD4 expression in clinical breast cancer samples.

Fluorouracil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-195 [16]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Key Molecule: hsa-miR-15b-5p [17]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Key Molecule: hsa-miR-206 [18]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• 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: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-206 downregulation modulates 5-FU resistance in HCT116 cells by upregulating Bcl-2.

Key Molecule: hsa-mir-21 [19]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 can mediate the drug resistance to 5-FU by inhibiting its target PDCD4, which can regulate the expression of ABCC5 and CD44 genes.

Key Molecule: Long non-protein coding RNA (snaR) [20]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNU-C4R cells; Colon; Homo sapiens (Human); CVCL_5111
• In Vitro Model: SNU-C5R cells; Colon; Homo sapiens (Human); CVCL_5112
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Down-regulation of snaR decreased cell death after 5-FU treatment, which indicates that snaR loss decreases in vitro sensitivity to 5-FU in human colon cancer cells.

Key Molecule: hsa-mir-21 [21], [22]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HT-29/5-FU cells; Colon; Homo sapiens (Human); CVCL_0I27
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells. And high miR-21 expression was significantly associated with poor therapeutic outcome (P = 0.0001) and adjuvant therapy was associated with improved survival in patients with low miR-21.

Key Molecule: hsa-mir-19b [23]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: KM12C cells; Colon; Homo sapiens (Human); CVCL_9547
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.

Key Molecule: hsa-mir-34 [24]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/5FU cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase Chk1 (CHK1) [16]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Key Molecule: Wee1-like protein kinase (WEE1) [16]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: Inhibition of miR195 sensitized resistant cells to 5-FU by downregulating WEE1 and CHk1.

Key Molecule: Nuclear factor kappa-B kinase subunit alpha inhibitor (IKKalpha) [17]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Dual-Luciferase Reporter Assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Key Molecule: DNA-binding factor KBF1 (p105) (NFKB1) [17]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: NF-kappaB signaling pathway; Inhibition; hsa04064
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Dual-Luciferase Reporter Assay
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR15b-5p resensitizes colon cancer cells to 5-fluorouracil by promoting apoptosis via the NF-kB/XIAP axis. miR15b-5p results in significant reductions in the levels of NF-kB1 and Ikk-alpha, two key modulators in inflammation and cell apoptosis.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [18]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• 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: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vivo Model: SCID mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTS assay; Flow cytometry assay
• Mechanism Description: miR-206 downregulation modulates 5-FU resistance in HCT116 cells by upregulating Bcl-2.

Key Molecule: Programmed cell death protein 4 (PDCD4) [19]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Regulation; hsa04151
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-21 can mediate the drug resistance to 5-FU by inhibiting its target PDCD4, which can regulate the expression of ABCC5 and CD44 genes.

Key Molecule: DNA mismatch repair protein Msh2 (MSH2) [22]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• 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 proliferation; Activation; hsa05200
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HT-29/5-FU cells; Colon; Homo sapiens (Human); CVCL_0I27
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-21 targeted the human mutS homolog2 (hMSH2), and indirectly regulated the expression of thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD). These results demonstrate that miR-21 may play an important role in the 5-FU resistance of colon cancer cells.

Key Molecule: Myb-related protein B (MYBL2) [23]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: KM12C cells; Colon; Homo sapiens (Human); CVCL_9547
• Experiment for Molecule Alteration: mRNA immunoprecipitation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.

Key Molecule: Splicing factor/proline/glutamine-rich (SFPQ) [23]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: KM12C cells; Colon; Homo sapiens (Human); CVCL_9547
• Experiment for Molecule Alteration: mRNA immunoprecipitation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-19b and miR-21 were over-expressed in 5-FU-resistant cells. Ingenuity pathway analysis of mRNA targets significantly (P < 0.05) indicated the category "Cell Cycle" as a probable area of the molecular and cellular function related with 5-FU resistance. Among candidate mRNA targets, SFPQ and MYBL2 have been linked to cell cycle functions.

Key Molecule: Transcription factor E2F3 (E2F3) [24]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/5FU cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3.

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [24]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: DLD-1/5FU cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: The ectopic expression of miR-34a in the 5-FU-resistant cells inhibited growth, as in the parental cells, and attenuated the resistance to 5-FU through the down-regulation of Sirt1 and E2F3.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-338-3p [25]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR338-3p/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR338-3p increased 5-FU resistance by reducing the expression of its target gene, mTOR; and miR338-3p inhibitor sensitized HT29 (mutant p53) and HCT116 p53-/- (deficient p53) cells by activating mTOR; and miR338-3p-mTOR-autophagy was in the competition with 5-FU-induced apoptosis and contributed to the subsequent 5-FU resistance. (Inhibition of mTOR induces autophagy and depresses apoptosis to confer resistance to 5-FU).

Key Molecule: E3 ubiquitin-protein ligase XIAP (XIAP) [17]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CellTiter-Glo Luminescent Cell Viability Assay; CCK8 assay; Flow cytometric analysis
• Mechanism Description: Overexpression of XIAP decreases the inhibitory effects of miR15b-5p on drug resistance in colon cancer cells. miR15b-5p mediates NF- B regulation by targeting the anti-apoptosis protein XIAP in vitro.

Key Molecule: hsa-mir-101 [10]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Colony formation assay; AO/EB double staining; Transwell invasion assay
• Mechanism Description: Upregulation of miR101 enhances the cytotoxic effect of anticancer drugs through inhibition of colon cancer cell proliferation. The upregulated expression of miR101 inhibited proliferation and migration, and increased the sensitivity of colon cancer cells to chemotherapy.

Key Molecule: hsa-mir-20b [26]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ADAM9/EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT116-R cells; Colon; Homo sapiens (Human); CVCL_AU09
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Annexin V apoptosis assay
• Mechanism Description: miR20b suppresses cell proliferation and apoptosis and regulates cell cycle progression by targeting ADAM9 in HCT116-R cells, miR20b reduces 5-FU resistance by suppressing the ADAM9/EGFR signaling pathway in colon cancer.

Key Molecule: hsa-mir-302a [27]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Trypan blue dye-exclusion assay; Annexin V-FITC apoptosis assay; Flow cytometer
• Mechanism Description: Both miR 302a and si IGF 1R inhibited Akt signaling. MiR 302a targeted IGF 1R and enhanced 5 FU induced cell death and viability inhibition in human colon cancer cells.

Key Molecule: hsa-mir-214 [28]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: miR-214 targeted heat shock protein 27 and could sensitize non-resistant colon cancer cells and 5-FU-resistant colon cancer cellsto 5-FU while overexpression of Hsp27 could block miR-214 with an effect on the sensitivity of colon cancer cells to 5-FU.

Key Molecule: hsa-miR-219a-5p [29]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: hsa-mir-494 [30]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: 5-Fu catabolic signaling pathway; Regulation; hsa00983
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-494 also negatively regulated endogenous DPYD expression in SW480 cells. Overexpression or knockdown of DPYD could attenuate miR-494 mediated 5-Fu sensitivity regulation, suggesting the dependence of DPYD regulation in miR-494 activity. miR-494 inhibited SW480/5-Fu derived xenograft tumors growth in vivo at present of 5-Fu.

Key Molecule: hsa-mir-320 [31]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Key Molecule: hsa-mir-34 [32]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• 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: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LDHA was shown to be a direct target of miR 34a. Overexpression of miR 34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re sensitization of 5 FU resistant cancer cells to 5 FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5 FU, suggesting that the miR 34a induced sensitization to 5 FU is mediated through the inhibition of LDHA. The current study showed that miR 34a is involved in sensitivity to 5 FU in part through its effects on LDHA expression.

Key Molecule: hsa-miR-142-3p [33]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Key Molecule: hsa-mir-140 [34]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family G2 (ABCG2) [33]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase mTOR (mTOR) [25]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: miR338-3p/mTOR signaling pathway; Activation; hsa05206
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis; Dual luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: miR338-3p increased 5-FU resistance by reducing the expression of its target gene, mTOR; and miR338-3p inhibitor sensitized HT29 (mutant p53) and HCT116 p53-/- (deficient p53) cells by activating mTOR; and miR338-3p-mTOR-autophagy was in the competition with 5-FU-induced apoptosis and contributed to the subsequent 5-FU resistance. (Inhibition of mTOR induces autophagy and depresses apoptosis to confer resistance to 5-FU).

Key Molecule: Myeloma cell metalloproteinase (ADAM9) [26]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: ADAM9/EGFR signaling pathway; Inhibition; hsa01521
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT116-R cells; Colon; Homo sapiens (Human); CVCL_AU09
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Annexin V apoptosis assay
• Mechanism Description: miR20b suppresses cell proliferation and apoptosis and regulates cell cycle progression by targeting ADAM9 in HCT116-R cells, miR20b reduces 5-FU resistance by suppressing the ADAM9/EGFR signaling pathway in colon cancer.

Key Molecule: Insulin-like growth factor 1 receptor (IGF1R) [27]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Inhibition; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye-exclusion assay; Annexin V-FITC apoptosis assay; Flow cytometer
• Mechanism Description: Both miR 302a and si IGF 1R inhibited Akt signaling. MiR 302a targeted IGF 1R and enhanced 5 FU induced cell death and viability inhibition in human colon cancer cells.

Key Molecule: Heat shock protein beta-1 (HSPB1) [28]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; TUNEL assay
• Mechanism Description: miR-214 targeted heat shock protein 27 and could sensitize non-resistant colon cancer cells and 5-FU-resistant colon cancer cellsto 5-FU while overexpression of Hsp27 could block miR-214 with an effect on the sensitivity of colon cancer cells to 5-FU.

Key Molecule: Sal-like protein 4 (SALL4) [29]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: Dihydropyrimidine dehydrogenase [NADP(+)] [30]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: 5-Fu catabolic signaling pathway; Regulation; hsa00983
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-494 also negatively regulated endogenous DPYD expression in SW480 cells. Overexpression or knockdown of DPYD could attenuate miR-494 mediated 5-Fu sensitivity regulation, suggesting the dependence of DPYD regulation in miR-494 activity. miR-494 inhibited SW480/5-Fu derived xenograft tumors growth in vivo at present of 5-Fu.

Key Molecule: Forkhead box protein M1 (FOXM1) [31]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Key Molecule: Lactate dehydrogenase A (LDHA) [32]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• 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: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: LDHA was shown to be a direct target of miR 34a. Overexpression of miR 34a reduced the expression of LDHA, probably through binding to the 3' untranslated region, leading to the re sensitization of 5 FU resistant cancer cells to 5 FU. Additionally, overexpression of LDHA rendered colon cancer cells resistant to 5 FU, suggesting that the miR 34a induced sensitization to 5 FU is mediated through the inhibition of LDHA. The current study showed that miR 34a is involved in sensitivity to 5 FU in part through its effects on LDHA expression.

Key Molecule: Prominin-1 (PROM1) [33]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Key Molecule: Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) [33]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vivo Model: HT-29 xenograft mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Annexin V assay
• Mechanism Description: The miR-142-3p was markedly decreased in coloncancer specimens, in which it was negatively correlated withthe expression of CD133, Lgr5, and ABCG2. Transfection of miR-142-3p mimics in colon cancer cells downregulated cyclin D1expression, induced G1phase cell cycle arrest, and elevatedthe sensitivity of the cells to 5-fluorouracil. Furthermore,OCT4 suppressed miR-142-3p, and hypomethylation of theOCT4promoter was associated with a reduction in miR-142-3p.

Key Molecule: Histone deacetylase 4 (HDAC4) [34]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Fluorouracil
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Gemcitabine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-330 [35]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: Colo320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Sulforhodamide B (SRB) test assay
• Mechanism Description: Deoxycytidine kinase (dCk) is essential for phosphorylation of natural deoxynucleosides andanalogs, such as gemcitabine and cytarabine, two widely used anticancer compounds. miR-330 expression negatively correlated withdCk mRNA expression, suggesting a role of miR-330 in post-transcriptional regulationof dCk. Expression of miR-330 in various colon and lung cancer cell lines,as measured by QRT-PCR, varied five-fold between samples and correlated with in-vitro gemcitabineresistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Deoxycytidine kinase (DCK) [35]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Gemcitabine
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: Colo320 cells; Colon; Homo sapiens (Human); CVCL_1989
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• Experiment for Molecule Alteration: qRT -PCR
• Experiment for Drug Resistance: Sulforhodamide B (SRB) test assay
• Mechanism Description: Deoxycytidine kinase (dCk) is essential for phosphorylation of natural deoxynucleosides andanalogs, such as gemcitabine and cytarabine, two widely used anticancer compounds. miR-330 expression negatively correlated withdCk mRNA expression, suggesting a role of miR-330 in post-transcriptional regulationof dCk. Expression of miR-330 in various colon and lung cancer cell lines,as measured by QRT-PCR, varied five-fold between samples and correlated with in-vitro gemcitabineresistance.

Methotrexate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-224 [36]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.

Key Molecule: hsa-mir-215 [37]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Solute carrier family 4 member 4 (SLC4A4) [36]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatidate cytidylyltransferase 2 (CDS2) [36]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.

Key Molecule: m7GpppN-mRNA hydrolase (DCP2) [36]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.

Key Molecule: Galectin-related protein (GRP) [36]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.

Key Molecule: Histone acetyltransferase KAT6A (KAT6A) [36]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: The endogenous overexpression of CDS2, DCP2, HSPC159, MYST3 and SLC4A4 in MTX-resistant HT29 cells. Inhibition of miR-224 with anti-miR224 produced an increase in the mRNA levels of CDS2, HSPC159, MYST3 and SLC4A4. Decreased mRNA levels of SLC4A4, CDS2 and HSPC159 cause an increase in MTX sensitivity in HT29 cells.

Key Molecule: Dihydrofolate reductase (DHFR) [37]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Key Molecule: Thymidylate synthase (TYMS) [37]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Methotrexate
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-140 [34]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Histone deacetylase 4 (HDAC4) [34]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Methotrexate
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-140 is involved in the chemoresistance by reduced cell proliferation via G1 and G2 phase arrest mediated in part.

Oxaliplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-19b-3p [38]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.

Key Molecule: Cytoskeleton regulator RNA (CYTOR) [39]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-APC/PI Apoptosis assay
• Mechanism Description: Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.

Key Molecule: hsa-mir-34 [40]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: WST-1 assay; Flow cytometry assay
• Mechanism Description: miR-34a positively regulates OAZ2 transcription by directly targeting its 3UTR and OAZ2 Overexpression Effectively Rescues the Chemosensitivity Impaired by miR-34a Deficiency.

Key Molecule: hsa-mir-126 [41]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Solute carrier family 7 member 5 (SLC7A5) [41]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Mothers against decapentaplegic homolog 4 (SMAD4) [38]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: Annexin V-PE and 7-AAD double staining method to examine cell viabilityNA; CCK8 assay; Flow cytometric analysis
• Mechanism Description: miR19b-3p promotes colon cancer proliferation and oxaliplatin-based chemoresistance by targeting SMAD4.

Key Molecule: Receptor tyrosine-protein kinase erbB-4 (ERBB4) [39]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: AKT signaling pathway; Activation; hsa04151
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-APC/PI Apoptosis assay
• Mechanism Description: Linc00152 modulates the expression of ERBB4 through competitively binding miR193a-3p. AkT activation mediated by ERBB4 contributes to Linc00152-conferred L-OHP resistance, Linc00152 contributed to L-OHP resistance at least partly through activating AkT pathway.

Key Molecule: Ornithine decarboxylase antizyme 2 (OAZ2) [40]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HCT-8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: WST-1 assay; Flow cytometry assay
• Mechanism Description: miR-34a positively regulates OAZ2 transcription by directly targeting its 3UTR and OAZ2 Overexpression Effectively Rescues the Chemosensitivity Impaired by miR-34a Deficiency.

Key Molecule: Insulin receptor substrate 1 (IRS1) [41]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell invasion; Regulation; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Key Molecule: Target of Myb protein 1 (TOM1) [41]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: 293T cells; Breast; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Over-expression of miR-126 in colon cancer cell was able to inhibit cell proliferation, promote cell apoptosis and reduce the invasive ability. miR-126 significantly enhanced the sensitivity of the colon cancer cell to chemotherapeutic drug. It has been shown that IRS1, SLC75A and TOM1 were the potential target genes of miR-126 in colon cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-137 [42]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-137 chemosensitizes colon cancer cells to the chemotherapeutic drug OXA by targeting YBX1, miR137 was involved in repression of YBX1 expression through targeting its 3'-untranslated region. Down-regulation of miR137 conferred OXA resistance in parental cells, while over-expression of miR137 sensitized resistant cells to OXA, which was partly rescued by YBX1 siRNA.

Key Molecule: hsa-miR-409-3p [43]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: CCD-18Co cells; Colon; Homo sapiens (Human); CVCL_2379
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR 409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR 409-3p (+) the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR 409-3p. In a xenograft model using nude mice, we examined the effects of miR 409-3p on tumor growth during chemotherapy. miR 409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1.

Key Molecule: hsa-miR-219a-5p [29]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: hsa-mir-320 [31]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Y-box-binding protein 1 (YBX1) [42]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Oxaliplatin
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Dual luciferase assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: microRNA-137 chemosensitizes colon cancer cells to the chemotherapeutic drug OXA by targeting YBX1, miR137 was involved in repression of YBX1 expression through targeting its 3'-untranslated region. Down-regulation of miR137 conferred OXA resistance in parental cells, while over-expression of miR137 sensitized resistant cells to OXA, which was partly rescued by YBX1 siRNA.

Key Molecule: Beclin-1 (BECN1) [43]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: FHC cells; Colon; Homo sapiens (Human); CVCL_3688
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: RkO cells; Colon; Homo sapiens (Human); CVCL_0504
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: CCD-18Co cells; Colon; Homo sapiens (Human); CVCL_2379
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The overexpression of miR 409-3p inhibited Beclin-1 expression and autophagic activity by binding to the 3'-untranslated region of Beclin-1 mRNA. In addition, the overexpression of miR 409-3p (+) the chemosensitivity of the oxaliplatin-sensitive and oxaliplatin-resistant colon cancer cells. The restoration of Beclin-1 abrogated these effects of miR 409-3p. In a xenograft model using nude mice, we examined the effects of miR 409-3p on tumor growth during chemotherapy. miR 409-3p overexpression sensitized the tumor to chemotherapy, while inhibiting chemotherapy-induced autophagy in a manner dependent on Beclin-1.

Key Molecule: Sal-like protein 4 (SALL4) [29]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Oxaliplatin
• 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: SW480 cells; Colon; Homo sapiens (Human); CVCL_0546
• In Vitro Model: DLD1 cells; Colon; Homo sapiens (Human); CVCL_0248
• In Vitro Model: SW620 cells; Colon; Homo sapiens (Human); CVCL_0547
• In Vitro Model: CaCo2 cells; Colon; Homo sapiens (Human); CVCL_0025
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: NCM460 cells; Colon; Homo sapiens (Human); CVCL_0460
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Luciferase assay; Wound healing assay; Transwell assay; Flow cytometry assay
• Mechanism Description: The aberrant expression of miR-219-5p and Sall4 in colon cancer specimens, and confirmed that Sall4 was the direct target of miR-219-5p. Additionally, by aid of gain and loss of function assays, miR-219-5p was observed to play an inhibitory effect on cell proliferation, invasion and drug resistance.

Key Molecule: Forkhead box protein M1 (FOXM1) [31]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Oxaliplatin
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: Wnt/Beta-catenin signaling pathway; Inhibition; hsa04310
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-320 enhances the sensitivity of human colon cancer cells to chemoradiotherapy in vitro by targeting FOXM1.

Paclitaxel

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-125a [44]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: BALB/C nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-125a/b significantly inhibited ALDH1A3 and Mcl1 expression, reduced cell survival, and increased cell apoptosis in HT29-taxol cells. Chemoresistance to paclitaxel is initiated by the downregulation of miR-125a/b expression, which subsequently upregulates ALDH1A3 and Mcl1 expression to promote survival of CSCs.

Key Molecule: hsa-mir-125b [44]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vivo Model: BALB/C nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-125a/b significantly inhibited ALDH1A3 and Mcl1 expression, reduced cell survival, and increased cell apoptosis in HT29-taxol cells. Chemoresistance to paclitaxel is initiated by the downregulation of miR-125a/b expression, which subsequently upregulates ALDH1A3 and Mcl1 expression to promote survival of CSCs.

Key Molecule: hsa-mir-22 [45]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-22 enhanced the anticancer effect of paclitaxel in the p53-mutated cells through increasing cell apoptosis and reducing cell proliferation and survival. The anticancer role of miR-22 was mediated by activation of PTEN signaling, subsequent inhibition of Akt Ser473 phosphorylation and MTDH expression, as well as upregulation of Bax and active caspase-3 levels.

Key Molecule: hsa-mir-203 [46]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• 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: PI3K signaling pathway; Regulation; hsa04151
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: RT-PCR; Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: the tumor suppressive role of miR-203 was mediated by negatively regulating Akt2 protein expression through mRNA degradation. The inhibition of Akt2 activity downregulated the protein expression of its downstream molecules involved in chemoresistance, such as MTDH and HSP90 genes.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Aldehyde dehydrogenase 6 (ALDH6) [44]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• 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: Overexpression of miR-125a/b significantly inhibited ALDH1A3 and Mcl1 expression, reduced cell survival, and increased cell apoptosis in HT29-taxol cells. Chemoresistance to paclitaxel is initiated by the downregulation of miR-125a/b expression, which subsequently upregulates ALDH1A3 and Mcl1 expression to promote survival of CSCs.

Key Molecule: Induced myeloid leukemia cell differentiation protein Mcl-1 (MCL1) [44]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Paclitaxel
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• 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: Overexpression of miR-125a/b significantly inhibited ALDH1A3 and Mcl1 expression, reduced cell survival, and increased cell apoptosis in HT29-taxol cells. Chemoresistance to paclitaxel is initiated by the downregulation of miR-125a/b expression, which subsequently upregulates ALDH1A3 and Mcl1 expression to promote survival of CSCs.

Key Molecule: Phosphatase and tensin homolog (PTEN) [45]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Paclitaxel
• 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: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Overexpression of miR-22 enhanced the anticancer effect of paclitaxel in the p53-mutated cells through increasing cell apoptosis and reducing cell proliferation and survival. The anticancer role of miR-22 was mediated by activation of PTEN signaling, subsequent inhibition of Akt Ser473 phosphorylation and MTDH expression, as well as upregulation of Bax and active caspase-3 levels.

Key Molecule: RAC-beta serine/threonine-protein kinase (AKT2) [46]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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 proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: PI3K signaling pathway; Regulation; hsa04151
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: HT-29 cells; Colon; Homo sapiens (Human); CVCL_0320
• In Vitro Model: HCT15 cells; Colon; Homo sapiens (Human); CVCL_0292
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The tumor suppressive role of miR-203 was mediated by negatively regulating Akt2 protein expression through mRNA degradation. The inhibition of Akt2 activity downregulated the protein expression of its downstream molecules involved in chemoresistance, such as MTDH and HSP90 genes.

Raltitrexed

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-215 [37]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Raltitrexed
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Dihydrofolate reductase (DHFR) [37]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Raltitrexed
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Key Molecule: Thymidylate synthase (TYMS) [37]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Raltitrexed
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: p53 signaling pathway; Activation; hsa04115
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis; Immunofluorescence analysis
• Experiment for Drug Resistance: WST-1 assay
• Mechanism Description: miR-215, through the suppression of DTL expression, induces a decreased cell proliferation by causing G2-arrest, thereby leading to an increase in chemoresistance to MTX and TDX.

Sunitinib

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-296 [3]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Sunitinib
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Response evaluation criteria in solid tumors assay
• Mechanism Description: The patients with decrease in miR-296 at 4 weeks may reflect a more aggressive tumor phenotype with increased metastasis and tumor cell invasiveness. The loss of miR-296 may be one of the mechanisms for primary resistance of colorectal cancer to chemotherapy.

Talazoparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Oxalosuccinate decarboxylase (IDH1) [47]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• 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.

Vincristine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-15 [48]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-15a and Mir-16 reverse drug resistance in colon cancer cells, possibly by down-regulating the expression of Bcl-2 protein.

Key Molecule: hsa-mir-16 [48]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: miR-15a and Mir-16 reverse drug resistance in colon cancer cells, possibly by down-regulating the expression of Bcl-2 protein.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [48]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Sensitive Drug: Vincristine
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: HCT8 cells; Colon; Homo sapiens (Human); CVCL_2478
• 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-15a and Mir-16 reverse drug resistance in colon cancer cells, possibly by down-regulating the expression of Bcl-2 protein.

Clinical Trial Drug(s) 7 drug(s) in total

Hydroxycamptothecin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-506 [49]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Hydroxycamptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: SW1116/HCPT; Colon; Homo sapiens (Human); CVCL_0544
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 over-expression in established HCPT-resistant colon cancer cell line confers resistance to HCPT by inhibiting PPARalpha expression.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Peroxisome proliferator-activated receptor alpha (PPARA) [49]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Hydroxycamptothecin
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: SW1116 cells; Colon; Homo sapiens (Human); CVCL_0544
• In Vitro Model: SW1116/HCPT; Colon; Homo sapiens (Human); CVCL_0544
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-506 over-expression in established HCPT-resistant colon cancer cell line confers resistance to HCPT by inhibiting PPARalpha expression.

Agerafenib

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) [50]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Agerafenib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: A375 cells; Skin; Homo sapiens (Human); CVCL_0132
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of Agerafenib by aberration of the drug's therapeutic target

BAY1161909

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: BAY1161909
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of BAY1161909 by unusual activation of pro-survival pathway.

LY2780301

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: PI3-kinase alpha (PIK3CA) [52]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.E545K (c.1633G>A)
• Sensitive Drug: LY2780301
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: .; .
• In Vivo Model: Female athymic nude-Foxn1 nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Pharmacokinetic studies; Pharmacokinetic studies; Antitumor activity

PLX4720

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) [53]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: PLX4720
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of PLX4720 by aberration of the drug's therapeutic target

Trichostatin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-181a [54]

• Resistant Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Key Molecule: hsa-miR-199a-5p [54]

• Resistant Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Key Molecule: hsa-mir-30d [54]

• Resistant Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: J82 cells; Bladder; Homo sapiens (Human); CVCL_0359
• In Vitro Model: UM-UC-3 cells; Bladder; Homo sapiens (Human); CVCL_1783
• Experiment for Molecule Alteration: RT-PCR; qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [54]

• Resistant Disease: Colon carcinoma [ICD-11: 2B90.2]
• Molecule Alteration: Expression; Up-regulation
• Resistant Drug: Trichostatin A
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: GRP78 up-regulation is a major contributor to tumorigenesis and therapeutic resistance, miR-30d, miR-181a and miR-199a-5p regulate GRP78 and that their decreased expression in tumor cells results in increased GRP78 levels, which in turn promotes tumorigenesis and therapeutic resistance.

VS-5584

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: PI3-kinase alpha (PIK3CA) [55]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.E542K (c.1624G>A)
• Sensitive Drug: VS-5584
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SNU869 cells; Biliary tract; Homo sapiens (Human); CVCL_5101
• In Vitro Model: SNU478 cells; Biliary tract; Homo sapiens (Human); CVCL_5065
• In Vitro Model: SNU308 cells; Biliary tract; Homo sapiens (Human); CVCL_5048
• In Vitro Model: SNU245 cells; Biliary tract; Homo sapiens (Human); CVCL_5038
• In Vitro Model: SNU1196 cells; Biliary tract; Homo sapiens (Human); CVCL_5015
• In Vitro Model: SNU1079 cells; Biliary tract; Homo sapiens (Human); CVCL_5008
• In Vitro Model: SET-2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: Athymic BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.E542K (c.1624G>A) in gene PIK3CA cause the sensitivity of VS-5584 by aberration of the drug's therapeutic target

Preclinical Drug(s) 7 drug(s) in total

BAY1217389

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: BAY1217389
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of BAY1217389 by unusual activation of pro-survival pathway.

GDC0879

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [56]

• Resistant Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.N581Y (c.1741A>T)
• Resistant Drug: GDC0879
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.N581Y (c.1741A>T) in gene BRAF cause the resistance of GDC0879 by aberration of the drug's therapeutic target

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) [56]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: GDC0879
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Female nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting assay
• Experiment for Drug Resistance: CellTiter-Glo assay
• Mechanism Description: The missense mutation p.V600E (c.1799T>A) in gene BRAF cause the sensitivity of GDC0879 by aberration of the drug's therapeutic target

MPI-0479605

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: MPI-0479605
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of MPI-0479605 by unusual activation of pro-survival pathway.

Mps-BAY2b

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: Mps-BAY2b
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of Mps-BAY2b by unusual activation of pro-survival pathway.

Mps1-IN-1

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: Mps1-IN-1
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of Mps1-IN-1 by unusual activation of pro-survival pathway.

Navitoclax/Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [57]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: Navitoclax/Trametinib
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HT29 Cells; Colon; Homo sapiens (Human); CVCL_A8EZ
• In Vitro Model: A549 cells; Lung; Homo sapiens (Human); CVCL_0023
• In Vitro Model: A2058 cells; Skin; Homo sapiens (Human); CVCL_1059
• In Vitro Model: HPAF-II cells; Pancreatic; Homo sapiens (Human); CVCL_0313
• In Vitro Model: H23 cells; Lung; Homo sapiens (Human); CVCL_1547
• In Vitro Model: WiDR cells; Colon; Homo sapiens (Human); CVCL_2760
• In Vitro Model: SW1573 cells; Lung; Homo sapiens (Human); CVCL_1720
• In Vitro Model: KHM-5M cells; Pleural effusion; Homo sapiens (Human); CVCL_2975
• In Vitro Model: WM793 cells; N.A.; Homo sapiens (Human); CVCL_8787/CVCL_5414
• In Vitro Model: SkMEL-2 cells; Skin; Homo sapiens (Human); CVCL_0069
• In Vitro Model: PANC 0203 cells; Pancreas; Homo sapiens (Human); CVCL_1633
• In Vitro Model: MOR/CPR cells; Lung; Homo sapiens (Human); CVCL_2620
• In Vitro Model: MM415 cells; Lymph node; Homo sapiens (Human); CVCL_2608
• In Vitro Model: HTC-C3 cells; Pleural effusion; Homo sapiens (Human); CVCL_2273
• In Vitro Model: HCC364 cells; Lung; Homo sapiens (Human); CVCL_5134
• In Vitro Model: H2347 cells; Lung; Homo sapiens (Human); CVCL_1550
• In Vitro Model: Calu-1 cells; Lung; Homo sapiens (Human); CVCL_0608
• In Vitro Model: CAL-12T cells; Lung; Homo sapiens (Human); CVCL_1105
• In Vivo Model: NOD-SCID female mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis; qPCR
• Experiment for Drug Resistance: CellTiter-Glo assay; Caspase3/7-Glo iuminescent assay

NTRC 0066-0

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: NTRC 0066-0
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of NTRC 0066-0 by unusual activation of pro-survival pathway.

Investigative Drug(s) 2 drug(s) in total

NMS-P715

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Catenin beta-1 (CTNNB1) [51]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: IF-deletion; p.S45delS (c.133_135delTCT)
• Sensitive Drug: NMS-P715
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HCT116 cells; Colon; Homo sapiens (Human); CVCL_0291
• In Vitro Model: SW48 cells; Colon; Homo sapiens (Human); CVCL_1724
• In Vitro Model: TOV-21G cells; Ovary; Homo sapiens (Human); CVCL_3613
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: TOV-112D cells; Ovary; Homo sapiens (Human); CVCL_3612
• In Vitro Model: LS 174T cells; Colon; Homo sapiens (Human); CVCL_1384
• In Vitro Model: A427 cells; Lung; Homo sapiens (Human); CVCL_1055
• In Vivo Model: Mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Gene set analysis
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: The if-deletion p.S45delS (c.133_135delTCT) in gene CTNNB1 cause the sensitivity of NMS-P715 by unusual activation of pro-survival pathway.

PKI-587

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Serine/threonine-protein kinase B-raf (BRAF) [58]

• Sensitive Disease: Colon cancer [ICD-11: 2B90.1]
• Molecule Alteration: Missense mutation; p.V600E (c.1799T>A)
• Sensitive Drug: PKI-587
• Experimental Note: Identified from the Human Clinical Data

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