Disease Information

General Information of the Disease (ID: DIS00096)

• Name: Prostate cancer
• ICD: ICD-11: 2C82

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 13 drug(s) in total

Doxorubicin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Pyruvate kinase L/R (PKLR) [1]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 5.48E-20; Fold-change: 7.15E-01; Z-score: 1.03E+01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Metabolic pathways; Activation; hsa01100
• Cell Pathway Regulation: Transcriptional misregulation in cancer; Activation; hsa05202
• In Vivo Model: 6-week-old male nude mice, with LASCPC01 cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Our study found significant correlations between ROMO1 and NE-related gene upregulation in PCa after ADT, which may have been caused by the nuclear translocation of PKLR and its interaction with the MYCN/MAX complex to promote ROMO1 and NE marker expression. Importantly, we found that this interaction decreased after treatment with a putative MYCN inhibitor. These data suggest that PKLR may also act as a transcription cofactor of MYCN, in addition to acting as a kinase, similar to PKM2, which acts as a transcription cofactor to activate hypoxia-inducible factor-1A (HIF1A) to promote castration resistance [22].

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: PCGEM1 prostate-specific transcript (PCGEM1) [15]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.91E-09; Fold-change: 1.52E+00; Z-score: 6.12E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: Northern blotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: PCGEM1overexpression in LNCaP cell culturemodel results in the inhibition of apoptosis induced by doxorubicin (DOX). Induction of p53 and p21Waf1/Cip1by DOX were delayed in LNCaP cells stably overexpressing PCGEM1(LNCaP-PCGEM1cells) compared tocontrol LNCaP cells.

Key Molecule: LOXL1 antisense RNA 1 (LOXL1-AS1) [27]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.33E-01; Fold-change: -3.94E-02; Z-score: -7.86E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [19]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.18E-07; Fold-change: 1.22E-01; Z-score: 6.14E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: However, higher concentrations of probenecid (500 uM) failed to demonstrate a chemosensitizing effect. Consistent with this lower chemosensitizing efficacy in higher-concentration probenecid treatment, we observed that the expression of ABCG2, a drug-efflux transporter, increased in a dose-dependent manner following probenecid treatment. Thus, probenecid could enhance the chemosensitivity of 3D-cultured prostate cancer cells, but not at higher concentr.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor (EGFR) [27]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.43E-04; Fold-change: -1.42E-01; Z-score: -3.79E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: LncRNA LOXL1-AS1/miR-let-7a-5p/EGFR-related pathway regulates the doxorubicin resistance of prostate cancer DU-145 cells.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family B5 (ABCB5) [30]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Doxorubicin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.06E-05; Fold-change: -1.09E-01; Z-score: -4.94E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: DU-145Nox1 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Immunohistochemistry assay
• Experiment for Drug Resistance: Annexin V staining assay
• Mechanism Description: In DU-145Nox1 tumor spheroids, expression of HIF-1alpha as well as P-gp was significantly decreased as compared to DU-145 spheroids, which resulted in an increased retention of the anticancer agent doxorubicin. Pretreatment with the free radical scavengers vitamin E and vitamin C increased the expression of P-gp as well as HIF-1alpha in Nox-1-overexpressing cells, whereas no effect of free radical scavengers was observed on mdr-1 mRNA expression.

Bicalutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Protocadherin beta-9 (PCDHB9) [3]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Bicalutamide
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.81E-02; Fold-change: 7.01E-02; Z-score: 2.42E+00
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: LN229 cells; Brain; Homo sapiens (Human); CVCL_0393
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Bicalutamide has been widely used as a first-line treatment for PCa. Although patients initially show a favorable response to bicalutamide treatment, PCa eventually acquires bicalutamide resistance. Several factors have been shown to be involved in bicalutamide resistance. However, the mechanism of bicalutamide resistance is not fully understood. In this study, the knockdown of protocadherin B9 reduced nuclear AR translocation and bicalutamide resistance in androgen-dependent LNCaP cells in the presence of DHT. The overexpression of protocadherin B9 had no effect on bicalutamide resistance in androgen-independent DU145 cells. These results further indicate that protocadherin B9 is involved in bicalutamide resistance through the modulation of AR signaling. Taken together, our findings suggest that protocadherin B9 targeted therapy could be more effective therapy than bicalutamide alone for patients with PCa.

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Androgen receptor (AR) [43]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Bicalutamide
• Molecule Alteration: Missense mutation; p.W742L (c.2225G>T)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 2.07 Å; PDB: 5CJ6
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.70 Å; PDB: 2AX8

RMSD: 0.43; TM score: 0.99443; Amino acid change: W742L

• Experimental Note: Identified from the Human Clinical Data

Key Molecule: Androgen receptor (AR) [43]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Bicalutamide
• Molecule Alteration: Missense mutation; p.W742C (c.2226G>T)
• Experimental Note: Identified from the Human Clinical Data

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Squalene epoxidase (SQLE) [44]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Bicalutamide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male NOD/SCID nude mice, With LNCaP, C4-2B, and C4-2B_shSQLE cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In our study, we found that the expression level of SQLE was significantly increased in bicalutamide-resistant-C4-2B cells compared to LNCaP cells. SQLE knockdown partly restored the sensitivity of drug-resistant cells to bicalutamide and reduced lymph node metastasis by inhibiting fatty acid oxidation in mitochondria. We also found that terbinafine, the specific inhibitor of SQLE, can enhance the sensitivity of prostate cancer cells to bicalutamide.

Docetaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: L-glutamine amidohydrolase (GLS) [4]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.08E-01; Fold-change: 5.66E-02; Z-score: 1.67E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: 293 T cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Mechanistically, Gln deprivation reduced OXPHOS and ATP levels, causing a disturbance in cell cycle progression. Genetic and chemical inhibition of the Gln-metabolism key protein GLS1 could validate the Gln deprivation results, thereby representing a valid therapeutic target. Moreover, immunohistological investigation of GLS1 revealed a high-expressing GLS1 subgroup post-docetaxel failure, exhibiting low overall survival. This subgroup presents an intriguing opportunity for targeted therapy focusing on glutamine metabolism.

Key Molecule: Hexokinase 2 (HK2) [56]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: SUMOylated; K315
• Experimental Note: Identified from the Human Clinical Data
• In Vivo Model: Prostate cancer patients; Homo Sapiens
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell prognosis assay
• Mechanism Description: Here, we report that SUMOylation regulates the binding of hexokinase 2 to mitochondria. We find that hexokinase 2 can be SUMOylated at K315 and K504.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Metastasis-associated protein MTA1 (MTA1) [7]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.16E-01; Fold-change: 4.86E-02; Z-score: 1.64E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MTA1 signaling pathway; Activation; hsa05206
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Promoter reporter assay; Western blot analysis
• Experiment for Drug Resistance: ELISA; MTT assay
• Mechanism Description: Regulation of docetaxel sensitivity in prostate cancer cells by hsa-miR125a-3p via modulation of metastasis-associated protein 1 signaling, MTA1 is a direct target of hsa-mir125a-3p in pca cells.

Key Molecule: Apoptosis regulator Bcl-2 (BCL2) [8]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.29E-02; Fold-change: 4.09E-02; Z-score: 2.60E+00
• 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: miR-34a regulates BCL-2 and may, in part, regulate response to docetaxel. miR-34a was significantly decreased in prostate cancer versus normal tissues; in biochemical recurrence versus non-recurrence tissue and in metastatic versus primary disease prostate tissue. We confirmed BCL-2 as a target of miR-34a, by manipulating miR-34a expression in our parent and docetaxel resistant cell lines and subsequently assessing BCL-2 levels. Specifically, upon inhibition of miR-34a in sensitive parent cells (PC3 and 22Rv1) we observed an increase in BCL-2 expression, whereas mimicking miR-34a expression in docetaxel-resistant cells (PC3RD and 22Rv1RD) resulted in decreased BCL-2 expression.

Key Molecule: A-kinase anchor protein 12 (AKAP12) [17]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.51E-02; Fold-change: 1.30E-01; Z-score: 1.86E+00
• Experimental Note: Identified from the Human Clinical 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; Scratch Wound healing assay; Transwell Invasion assay; Flow cytometry assay
• Mechanism Description: Knockdown of MALAT1 in DTX-resistant PCa cells up-regulated miR-145-5p as well as suppressed AkAP12 expression, further inhibited cell viability and induced apoptosis.

Key Molecule: Tumor necrosis factor ligand superfamily member 10 (TNFSF10) [21]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 9.66E-01; Fold-change: -7.23E-04; Z-score: -4.34E-02
• 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: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: LTAD cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot analysis; Immunohistochemistry assay
• Experiment for Drug Resistance: TUNEL assay; MTS assay
• Mechanism Description: Androgen-induced Long Noncoding RNA (LncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells.suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells.SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10 These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis.

Key Molecule: Protein transport protein Sec23A (SEC23A) [28]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.83E-01; Fold-change: -4.00E-02; Z-score: -1.10E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Annexin V-PE Apoptosis assay
• Mechanism Description: miR375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1.

Key Molecule: Tumor protein p73 (TP73) [31]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.84E-04; Fold-change: -1.18E-01; Z-score: -4.02E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Luciferase reporter assay; Western blot analysis
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: microRNA-323 upregulation promotes prostate cancer growth and docetaxel resistance by repressing p73.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-323 [31]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometric analysis
• Mechanism Description: microRNA-323 upregulation promotes prostate cancer growth and docetaxel resistance by repressing p73.

Key Molecule: hsa-mir-181a [51]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C4-2B cells; Prostate; Homo sapiens (Human); CVCL_4784
• In Vitro Model: TaxR cells; Prostate; Homo sapiens (Human); CVCL_4V97
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Beckman Coulter method; Rhodamine Assay; Cell Death ELISA
• Mechanism Description: Overexpression of miR181a in prostate cancer cells contributes to their resistance to docetaxel, this is due, in part, to modulation of p53 phosphorylation and apoptosis.

Key Molecule: hsa-miR-125a-3p [7]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: MTA1 signaling pathway; Activation; hsa05206
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: ELISA; MTT assay
• Mechanism Description: Regulation of docetaxel sensitivity in prostate cancer cells by hsa-miR125a-3p via modulation of metastasis-associated protein 1 signaling, MTA1 is a direct target of hsa-mir125a-3p in pca cells.

Key Molecule: hsa-mir-375 [28]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Annexin V-PE Apoptosis assay
• Mechanism Description: miR375 induces docetaxel resistance in prostate cancer by targeting SEC23A and YAP1.

Key Molecule: hsa-mir-195 [52]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell colony; Activation; hsa05200
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: miR-195 improved the sensitivity of resistant PC cells to DOC by suppressing CLU.

Key Molecule: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) [17]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: MTT assay; Scratch Wound healing assay; Transwell Invasion assay; Flow cytometry assay
• Mechanism Description: Knockdown of MALAT1 in DTX-resistant PCa cells up-regulated miR-145-5p as well as suppressed AkAP12 expression, further inhibited cell viability and induced apoptosis.

Key Molecule: SOCS2 antisense RNA 1 (SOCS2-AS1) [21]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• 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: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: LTAD cells; Prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: TUNEL assay; MTS assay
• Mechanism Description: Androgen-induced Long Noncoding RNA (LncRNA) SOCS2-AS1 Promotes Cell Growth and Inhibits Apoptosis in Prostate Cancer Cells.suppressor of cytokine signaling 2-antisense transcript 1 (SOCS2-AS1), the expression of which was higher in castration-resistant prostate cancer model cells.SOCS2-AS1 promoted castration-resistant and androgen-dependent cell growth. We found that SOCS2-AS1 knockdown up-regulated genes related to the apoptosis pathway, including tumor necrosis factor superfamily 10 (TNFSF10), and sensitized prostate cancer cells to docetaxel treatment. Moreover, we also demonstrated that SOCS2-AS1 promotes androgen signaling by modulating the epigenetic control for AR target genes including TNFSF10 These findings suggest that SOCS2-AS1 plays an important role in the development of castration-resistant prostate cancer by repressing apoptosis.

Key Molecule: hsa-mir-34 [8]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Acid phosphatase assay
• Mechanism Description: miR-34a regulates BCL-2 and may, in part, regulate response to docetaxel. miR-34a was significantly decreased in prostate cancer versus normal tissues; in biochemical recurrence versus non-recurrence tissue and in metastatic versus primary disease prostate tissue. We confirmed BCL-2 as a target of miR-34a, by manipulating miR-34a expression in our parent and docetaxel resistant cell lines and subsequently assessing BCL-2 levels. Specifically, upon inhibition of miR-34a in sensitive parent cells (PC3 and 22Rv1) we observed an increase in BCL-2 expression, whereas mimicking miR-34a expression in docetaxel-resistant cells (PC3RD and 22Rv1RD) resulted in decreased BCL-2 expression.

Key Molecule: hsa-mir-205 [47], [53]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay; Flow cytometry assay
• Mechanism Description: Docetaxel-resistant cells showed a reduced E-cadherin and an increased vimentin expression accompanied by induced expression of stem cell markers compared with parental cells. Decreased Expression of miR-200c and miR-205 Is Responsible for E-Cadherin Loss in Chemotherapy-Resistant Cells. And miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: Growth arrest specific 5 (GAS5) [54]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Fluorescence microscopy test apoptosis assay
• Mechanism Description: Transient expression of GAS5 enhances apoptosis and decreases the survival of 22Rv1 cells, forced variation of GAS5 gene expression can modulate cellular responses to various apoptotic stimuli, including a range of chemotherapeutic drugs.

Key Molecule: hsa-mir-200c [53]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Docetaxel-resistant cells showed a reduced E-cadherin and an increased vimentin expression accompanied by induced expression of stem cell markers compared with parental cells. Decreased Expression of miR-200c and miR-205 Is Responsible for E-Cadherin Loss in Chemotherapy-Resistant Cells.

Key Molecule: hsa-mir-31 [47]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: hsa-mir-21 [55]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Programmed cell death 4 (PDCD4), is a novel suppressor of tumorigenesis, tumor progression and invasion. miR-21 can directly down-regulate the expression of PDCD4 by targeting its 3'UTR in PC3 cells. PDCD4, a direct target gene of miR-21, could mediate chemoresistance to docetaxel in PC3 cells.

Key Molecule: hsa-miR-148a [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: To confirm the results from global miRNA profiling, four miRNAs found to be decreased in the cells and exosomes of at least two of the three docetaxel-resistant cell line variants were selected for validation by qPCR. The expression of miR-598, miR-148a, miR-34a, and miR-146a confirmed the same trends as demonstrated in the global profiling.

Key Molecule: hsa-miR-191 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Increased expression of hsa-mir-191.

Key Molecule: hsa-miR-1267 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-1267 is decreased

Key Molecule: hsa-miR-301b [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-301b is increased.

Key Molecule: hsa-miR-454 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-454 is increased.

Key Molecule: hsa-miR-767 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-767 is increased.

Key Molecule: hsa-miR-598 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-598 is increased.

Key Molecule: hsa-miR-455 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-455 is increased.

Key Molecule: hsa-miR-146b [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-146b is increased.

Key Molecule: hsa-miR-486-1 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-486-1 is decreased

Key Molecule: hsa-miR-194-1 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-194-1 is increased.

Key Molecule: hsa-miR-9-1 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-9-1 is decreased

Key Molecule: hsa-miR-105-1 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-105-1 is decreased

Key Molecule: hsa-miR-95 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-95 is decreased

Key Molecule: hsa-miR-15a [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-15a is increased.

Key Molecule: hsa-miR-25 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-25 is decreased.

Key Molecule: hsa-miR-26b [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-26b is increased.

Key Molecule: hsa-miR-96 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-96 is decreased.

Key Molecule: hsa-miR-99a [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-99a is increased.

Key Molecule: hsa-miR-152 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-152 is increased.

Key Molecule: hsa-miR-146a [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-146a is increased.

Key Molecule: hsa-miR-301a [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-301a is increased.

Key Molecule: hsa-miR-30e [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-30e is increased.

Key Molecule: hsa-miR-342 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-342 is increased.

Key Molecule: hsa-miR-135b [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-135b is decreased.

Key Molecule: hsa-miR-196b [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-196b is decreased.

Key Molecule: hsa-miR-20b [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-20b is decreased.

Key Molecule: hsa-miR-489 [50]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Docetaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qPCR
• Mechanism Description: Global microRNA profiling was performed on docetaxel-resistant and sensitive cell lines to identify candidate circulating microRNA biomarkers. Custom Taqman Array MicroRNA cards were used to measure the levels of 46 candidate microRNAs in plasma/serum samples, collected before and after docetaxel treatment, from 97 CRPC patients. Expression of hsa-mir-489 is decreased.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Forkhead box protein O3 (FOXO3) [13]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.55E-01; Fold-change: 1.97E-02; Z-score: 1.16E+00
• 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay; TUNEL assay; Flow cytometry assay
• Mechanism Description: miR-223-3p inhibitor sensitized prostatic cancer mouse model to docetaxel by increasing the expression of FOXO3.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Cancer susceptibility 2 (CASC2) [20]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Docetaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.71E-02; Fold-change: 1.02E-01; Z-score: 1.99E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: ERK signaling pathway; Regulation; N.A.
• Cell Pathway Regulation: RTK signaling pathway; Inhibition; hsa04015
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay; Flow cytometer assay
• Mechanism Description: CASC2 directly targets miR183 to inhibit its expression. SPRY2 is regarded as a negative regulator RTk signaling pathway, antagonizing cell migration and/or cellular differentiation occurring through the ERk signaling. CASC2 competes with SPRY2 for miR183 binding to rescue the expression of SPRY2 in PC cells, thus suppressing the cell proliferation and promoting the apoptosis of PC cells, finally enhancing PC cells chemo-sensitivity to docetaxel through SPRY2 downstream ERk signaling pathway.

Temsirolimus

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Growth arrest specific 5 (GAS5) [5]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Temsirolimus
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.54E-18; Fold-change: 5.36E-01; Z-score: 9.11E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: PNT2C2 cells; Prostate; Homo sapiens (Human); CVCL_4889
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: GAS5 assay; MTS assay
• Mechanism Description: First generation mTORC1, combined mTORC1/mTORC2 and dual PI3k/mTOR inhibitors all increased cellular GAS5 levels and inhibited culture growth in androgen-dependent (LNCaP) and androgen-sensitive (22Rv1) cell lines, but not in androgen-independent (PC-3 and DU 145) cell lines. The latter exhibited low endogenous GAS5 expression, and GAS5 silencing in LNCaP and 22Rv1 cells decreased the sensitivity to mTOR inhibitors, whereas transfection of GAS5 LncRNA sensitized PC-3 and DU 145 cells to these agents.

Olaparib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Prostate cancer associated transcript 1 (PCAT1) [9]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Olaparib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.05E-25; Fold-change: 3.43E+00; Z-score: 1.10E+01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE cells; Prostate; Homo sapiens (Human); CVCL_1736
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: WST assay
• Mechanism Description: PCAT-1 expressing cells exhibit a BRCA-like phenotype, resulting in cell sensitization to PARP1 inhibitors. In human prostate cancer tissues, high PCAT-1 expression predicts for low BRCA2 expression, supporting our observations in model systems.

Paclitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase Yes (YES1) [10]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.64E-01; Fold-change: 3.34E-03; Z-score: 1.72E-01
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: PC3/TXR cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; Luciferase reporter assay
• Experiment for Drug Resistance: MTT assay; Annexin V-FITC and PI Flow cytometry assay
• Mechanism Description: Overexpression of miR199a inhibited PTX resistance. YES1 was a target of miR199a, and overexpression of YES1 reversed the effect of miR199a in suppressing PTX resistance. In vivo, miR199a increased tumor PTX sensitivity.

Key Molecule: SLAIN motif-containing protein 1 (SLAIN1) [11]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.28E-04; Fold-change: 3.25E-01; Z-score: 4.11E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Caspase-3 signaling pathway; Activation; hsa04210
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo luminescent cell viability assay
• Mechanism Description: Restoration of miR-130a activated caspase-8 and increased the drug sensitivity in taxane-resistant prostate cancer cells, suggesting that miR-130a may become a potential target for therapy of taxane-resistant CRPC. Since the mechanism of the action of miR-130a was different from that of paclitaxel, a combination therapy of paclitaxel and miR-130a mimic may be effective in treatment of CRPC. Furthermore, it was reported that miR-130a expression was decreased in prostate cancer tissues. It is therefore possible that the restoration of miR-130a could be an effective approach for treating not only taxane-resistant prostate cancer but also prostate cancer with reduced expression of miR-130a.

Key Molecule: Transcription factor GATA6 (GATA6) [16]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Paclitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.12E-02; Fold-change: 1.34E-01; Z-score: 2.48E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• Experiment for Molecule Alteration: Western blot analysis; RT-qPCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Long non-coding RNA Linc00518 Can enhance GATA6 expression by suppressing miR-216b-5p expression to promotes paclitaxel resistance in the human prostate cancer.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ribosomal protein S6 kinase alpha-5 (RPS6KA5) [33]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Paclitaxel
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.96E-07; Fold-change: -1.87E-01; Z-score: -5.71E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• Cell Pathway Regulation: Cell migration; Inhibition; hsa04670
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• Cell Pathway Regulation: MSK1 signaling pathway; Inhibition; hsa04010
• In Vitro Model: PC3PR cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell Growth Assay
• Mechanism Description: MSk1 is a novel target gene of miR-148a in both PC3 and PC3PR cells and miR-148 attenuates paclitaxel-resistance of PC3PR cells by modulating MSk1 expression.

Cabazitaxel

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tubulin beta-3 chain (TUBB3) [12]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.82E-01; Fold-change: 2.20E-02; Z-score: 1.10E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: DU145-DR cells; Brain; Homo sapiens (Human); CVCL_4Y36
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression.

Key Molecule: Phosphatase and tensin homolog (PTEN) [12]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: DU145-DR cells; Brain; Homo sapiens (Human); CVCL_4Y36
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression.

Key Molecule: Mitogen-activated protein kinase 1 (MAPK1) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Key Molecule: Calcium/calmodulin-dependent protein kinase type II delta/gamma (CAMK2D/G) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Key Molecule: Eukaryotic elongation factor 2 kinase (eEF2K) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Key Molecule: Guanine nucleotide-binding protein G(i) subunit alpha-2 (GNAI2) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Key Molecule: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Expression; Up-regulation
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• Experiment for Molecule Alteration: Gene expression analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Key Molecule: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase beta-3 (PLCB3) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Key Molecule: 5'-AMP-activated protein kinase catalytic subunit alpha-1 (PRKAA1) [45]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cabazitaxel
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Phosphatase and tensin homolog (PTEN) [12]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cabazitaxel
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.27E-02; Fold-change: 1.09E-01; Z-score: 2.44E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: DU145-DR cells; Brain; Homo sapiens (Human); CVCL_4Y36
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression.

Key Molecule: Tubulin beta-3 chain (TUBB3) [12]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cabazitaxel
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: CAL27 cells; Oral; Homo sapiens (Human); CVCL_1107
• In Vitro Model: LOVO cells; Colon; Homo sapiens (Human); CVCL_0399
• In Vitro Model: BxPC-3 cells; Pancreas; Homo sapiens (Human); CVCL_0186
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vitro Model: DU145-DR cells; Brain; Homo sapiens (Human); CVCL_4Y36
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: TUBB3 expression was upregulated in DTX-resistant and CBZ-resistant cells. TUBB3 knockdown re-sensitized DTX-resistant cells to DTX and CBZ-resistant cells to CBZ. Additionally, TUBB3 knockdown re-sensitized DTX-resistant cell lines to CBZ, indicating that TUBB3 mediates cross-resistance between DTX and CBZ. Knockdown of TUBB3 enhanced PTEN expression, and PTEN knockout enhanced TUBB3 expression.

Cisplatin

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5) [14]

• Resistant Disease: Prostatic intraepithelial neoplasia [ICD-11: 2C82.2]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.95E-06; Fold-change: 1.89E-01; Z-score: 5.92E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCalpha concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance.

Key Molecule: BH3-interacting domain death agonist (BID) [22]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.58E-01; Fold-change: -7.54E-03; Z-score: -1.81E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [22]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.50E-03; Fold-change: -9.12E-02; Z-score: -3.18E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Bcl-2-like protein 11 (BCL2L11) [22]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.20E-04; Fold-change: -1.26E-01; Z-score: -3.89E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: BALB/c nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Branched-chain-amino-acid aminotransferase (BCAT1) [46]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR218 inhibited cell viability, migration, and invasion in PC3 and DU145 cells. Overexpression of BCAT1 decreased the chemosensitivity to CDDP treatment of PC3 and DU145 cells. The tumor suppressive role of miR218 was mediated by negatively regulating BCAT1 protein expression.

Key Molecule: Bcl-2-interacting killer (BIK) [22]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: Bcl-2-like protein 2 (BCL2L2) [47]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: Transcription factor E2F6 (E2F6) [47]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: G1/S-specific cyclin-D1 (CCND1) [48]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: ATP cell viability assay
• Mechanism Description: CCND1 may induce cisplatin resistance both through cell cycle control and inhibition of cellular apoptosis pathways, which have been previously observed37 and supported by our CCND1 knockdown study. The role of CCND1 in cell cycle control is well documented. CCND1 accumulates in cells at middle and late G1 phase and stimulate G1 progression to S phase. The proportion of parental cells in G1/0 correlated with the cisplatin sensitivity, with 833K cells having the highest G1/0 population cells and lowest EC50 value and GCT27 the lowest G1/0 population but highest EC50 score.

Key Molecule: Bcl-2-associated agonist of cell death (BAD) [14]

• Resistant Disease: Prostatic intraepithelial neoplasia [ICD-11: 2C82.2]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qRT-PCR; Western blotting assay
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Forced expression of the PCPH protein or, in particular, of the mt-PCPH oncoprotein increased the levels of phosphorylated PKCalpha concurrently with those of Ser70-phosphorylated and total Bcl-2 protein, thus promoting cisplatin resistance.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-218 [46]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell viability; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: PCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometric analysis
• Mechanism Description: Overexpression of miR218 inhibited cell viability, migration, and invasion in PC3 and DU145 cells. Overexpression of BCAT1 decreased the chemosensitivity to CDDP treatment of PC3 and DU145 cells. The tumor suppressive role of miR218 was mediated by negatively regulating BCAT1 protein expression.

Key Molecule: hsa-miR-17-92 [22]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: AKT/ERK signaling pathway; Activation; hsa04010
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• Cell Pathway Regulation: Cell invasion; Activation; hsa05200
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-17-92 cluster plays a crucial role in cell growth of the DU145 prostate cancer cells due to regulation of cellular apoptosis-related and proliferation-related proteins, and causes chemo-resistance to cisplatin via activating AkT signaling together with upregulating ERCC1 also contributed to development of cisplatin-resistance.

Key Molecule: hsa-mir-205 [47]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Key Molecule: hsa-mir-31 [47]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• In Vitro Model: WPE1-NA22 cells; Prostate; Homo sapiens (Human); CVCL_3810
• In Vitro Model: WPE1-NB11 cells; Prostate; Homo sapiens (Human); CVCL_3811
• In Vitro Model: WPE1-NB14 cells; Prostate; Homo sapiens (Human); CVCL_3812
• In Vitro Model: WPE1-NB26 cells; Prostate; Homo sapiens (Human); CVCL_3813
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: miR-205 and miR-31 regulate apoptosis in prostate cancer cells by targeting antiapoptotic proteins Bcl-w and E2F6.

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: ATP-binding cassette sub-family C2 (ABCC2) [19]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: However, higher concentrations of probenecid (500 uM) failed to demonstrate a chemosensitizing effect. Consistent with this lower chemosensitizing efficacy in higher-concentration probenecid treatment, we observed that the expression of ABCG2, a drug-efflux transporter, increased in a dose-dependent manner following probenecid treatment. Thus, probenecid could enhance the chemosensitivity of 3D-cultured prostate cancer cells, but not at higher concentr.

Key Molecule: Multidrug resistance-associated protein 1 (MRP1) [19]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: 22RV1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: However, higher concentrations of probenecid (500 uM) failed to demonstrate a chemosensitizing effect. Consistent with this lower chemosensitizing efficacy in higher-concentration probenecid treatment, we observed that the expression of ABCG2, a drug-efflux transporter, increased in a dose-dependent manner following probenecid treatment. Thus, probenecid could enhance the chemosensitivity of 3D-cultured prostate cancer cells, but not at higher concentr.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Matrix metalloproteinase-9 (MMP9) [24]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.62E-01; Fold-change: -2.74E-02; Z-score: -4.42E-01
• 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 viability; Inhibition; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• Cell Pathway Regulation: Epithelial mesenchymal transition signaling pathway; Inhibition; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: UTMD mediated miR 205 transfection increased the expression of caspase 9, cleaved caspase 9, cytochrome c and E cadherin, and decreased the expression of MMP 9 and p ERk,inhibiting PCa cell proliferation, migration and invasion, and promoted apoptosis modulated by cisplatin.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Lysosome-associated membrane glycoprotein 3 (LAMP3) [25]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 6.24E-01; Fold-change: -3.15E-02; Z-score: -4.95E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Lysosome disturbance caused by miR-205-mediated down-regulation of RAB27A and LAMP3 constraints the completion of the autophagic flux by compromising the maturation step and, consequently, interferes with the detoxifying capabilities by which PCa cells may become resistant to CDDP.

Key Molecule: Zinc finger E-box-binding homeobox 1 (ZEB1) [32]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.99E-03; Fold-change: -1.37E-01; Z-score: -3.47E+00
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-PCR; Western blot analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-128 binded to the 3'UTR of ZEB1 and inhibited its expression. And ZEB1 (+) PCa chemoresistance and invasion, while miR-128 could reverse that by down-regulated ZEB1. These indicated that miR-128-mediated sensitizing chemoresistance and inhibiting invasion of PCa cells by directly targeting ZEB1.

Key Molecule: Ras-related protein Rab-27A (RAP27A) [25]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Immunoblotting analysis
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Lysosome disturbance caused by miR-205-mediated down-regulation of RAB27A and LAMP3 constraints the completion of the autophagic flux by compromising the maturation step and, consequently, interferes with the detoxifying capabilities by which PCa cells may become resistant to CDDP.

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-mir-205 [24]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• 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 viability; Inhibition; hsa05200
• Cell Pathway Regulation: ERK signaling pathway; Inhibition; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: VCaP cells; Prostate; Homo sapiens (Human); CVCL_2235
• Experiment for Molecule Alteration: RT-qPCR
• Experiment for Drug Resistance: CCK8 assay; Flow cytometry assay
• Mechanism Description: UTMD mediated miR 205 transfection increased the expression of caspase 9, cleaved caspase 9, cytochrome c and E cadherin, and decreased the expression of MMP 9 and p ERk,inhibiting PCa cell proliferation, migration and invasion, and promoted apoptosis modulated by cisplatin.

Key Molecule: hsa-mir-128a [32]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Identified from the Human Clinical Data
• Cell Pathway Regulation: Cell invasion; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: HEK293T cells; Kidney; Homo sapiens (Human); CVCL_0063
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: miR-128 binded to the 3'UTR of ZEB1 and inhibited its expression. And ZEB1 (+) PCa chemoresistance and invasion, while miR-128 could reverse that by down-regulated ZEB1. These indicated that miR-128-mediated sensitizing chemoresistance and inhibiting invasion of PCa cells by directly targeting ZEB1.

Key Molecule: hsa-mir-205 [25]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SCID nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: RT-PCR
• Experiment for Drug Resistance: Flow cytometry assay
• Mechanism Description: Lysosome disturbance caused by miR-205-mediated down-regulation of RAB27A and LAMP3 constraints the completion of the autophagic flux by compromising the maturation step and, consequently, interferes with the detoxifying capabilities by which PCa cells may become resistant to CDDP.

Drug Sensitive Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: hsa-miR-32 [49]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cisplatin
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: RNA sequencing analysis; q-RT-PCR; Western blot; Chromatin immunoprecipitation
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Here, we found that KLF4 was induced by cisplatin in prostate cancer cells and that the increase in KLF4 promoted cell apoptosis. Further mechanistic studies revealed that KLF4 directly bound to the promoter of BIK, facilitating its transcription. Additionally, we also found that the gene encoding KLF4 was a direct target of miR-32-5p. The downregulation of miR-32-5p in response to cisplatin treatment promoted KLF4 expression, which resulted in a increase in the chemosensitivity of prostate cancer.

Sulforaphane

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Core histone macro-H2A.1 (H2AFY) [26]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Sulforaphane
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.25E-01; Fold-change: -3.58E-02; Z-score: -1.24E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: Knockdown of LINC01116 with siRNA decreased proliferation of prostate cancer cells, and significantly upregulated several genes including GAPDH (regulates glycolysis), MAP1LC3B2 (autophagy) and H2AFY (chromatin structure) and LncRNA LINC01116 is upregulated in a human prostate cancer cell line, is decreased by SFN treatment, and promotes cell proliferation in a human cancer cell line.

Key Molecule: Glyceraldehyde-3-phosphate dehydrogenase 1 (GAPDH) [26]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Sulforaphane
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.35E-05; Fold-change: -5.47E-02; Z-score: -4.95E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• Experiment for Molecule Alteration: qPCR
• Experiment for Drug Resistance: Cell proliferation assay
• Mechanism Description: Knockdown of LINC01116 with siRNA decreased proliferation of prostate cancer cells, and significantly upregulated several genes including GAPDH (regulates glycolysis), MAP1LC3B2 (autophagy) and H2AFY (chromatin structure) and LncRNA LINC01116 is upregulated in a human prostate cancer cell line, is decreased by SFN treatment, and promotes cell proliferation in a human cancer cell line.

Verteporfin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Transcriptional coactivator YAP1 (YAP1) [29]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Verteporfin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.45E-03; Fold-change: -4.71E-02; Z-score: -2.78E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Calu-3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vivo Model: Male BALB/c nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: WST-1 assay; Colony formation assay; Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells.

Key Molecule: Myb-related protein B (MYBL2) [29]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Verteporfin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.51E-02; Fold-change: -9.80E-02; Z-score: -2.22E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: HEp-2 cells; Skin; Homo sapiens (Human); CVCL_1906
• In Vitro Model: U251 cells; Brain; Homo sapiens (Human); CVCL_0021
• In Vitro Model: BT474 cells; Breast; Homo sapiens (Human); CVCL_0179
• In Vitro Model: A172 cells; Brain; Homo sapiens (Human); CVCL_0131
• In Vitro Model: U87 cells; Brain; Homo sapiens (Human); CVCL_0022
• In Vitro Model: H1299 cells; Lung; Homo sapiens (Human); CVCL_0060
• In Vitro Model: Calu-3 cells; Lung; Homo sapiens (Human); CVCL_0609
• In Vitro Model: HuTu80 cells; Small intestine; Homo sapiens (Human); CVCL_1301
• In Vivo Model: Male BALB/c nude mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis; qRT-PCR
• Experiment for Drug Resistance: WST-1 assay; Colony formation assay; Annexin V-FITC/PI Apoptosis assay
• Mechanism Description: MYBL2 expression was significantly upregulated in CRPC tissues and cell lines. Overexpression of MYBL2 could facilitate castration-resistant growth and metastatic capacity in androgen-dependent PCa cells by promoting YAP1 transcriptional activity via modulating the activity of the Rho GTPases RhoA and LATS1 kinase. Importantly, targeting MYBL2, or treatment with either the YAP/TAZ inhibitor Verteporfin or the RhoA inhibitor Simvastatin, reversed the resistance to ADT and blocked bone metastasis in CRPC cells.

Abiraterone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Androgen receptor (AR) [40]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Abiraterone
• Molecule Alteration: Structural variation; Copy number gain
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole genome sequencing assay; Exome sequencing assay
• Mechanism Description: Accordingly, AR amplification was detected in circulating cell-free DNA and was shown to be associated with enzalutamide and abiraterone treatment resistance in a cohort of 62 CRPC patients.

Key Molecule: Androgen receptor (AR) [40]

• Resistant Disease: Primary prostate cancer [ICD-11: 2C82.Z]
• Resistant Drug: Abiraterone
• Molecule Alteration: Structural variation; Copy number gain
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Whole genome sequencing assay; Exome sequencing assay
• Mechanism Description: Accordingly, AR amplification was detected in circulating cell-free DNA and was shown to be associated with enzalutamide and abiraterone treatment resistance in a cohort of 62 CRPC patients.

Apalutamide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Androgen receptor (AR) [41]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: Missense mutation; p.F877L (c.2629T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.44 Å; PDB: 5V8Q
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.69 Å; PDB: 8FH1

RMSD: 0.7; TM score: 0.99191; Amino acid change: F877L

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SHO male mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Chromatin immunoprecipitation assay
• Mechanism Description: The missense mutation p.F877L (c.2629T>C) in gene AR cause the resistance of Apalutamide by aberration of the drug's therapeutic target

Key Molecule: Androgen receptor (AR) [41]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: Missense mutation; p.F877L (c.2629T>C)
• Wild Type Structure: Method: X-ray diffraction; Resolution: 1.44 Å; PDB: 5V8Q
• Mutant Type Structure: Method: X-ray diffraction; Resolution: 1.69 Å; PDB: 8FH1

RMSD: 0.7; TM score: 0.99191; Amino acid change: F877L

• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SHO male mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Chromatin immunoprecipitation assay
• Mechanism Description: The missense mutation p.F877L (c.2629T>C) in gene AR cause the resistance of Apalutamide by aberration of the drug's therapeutic target

Key Molecule: Androgen receptor (AR) [41]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: Missense mutation; p.F877L (.
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vivo Model: SHO male mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Chromatin immunoprecipitation assay
• Mechanism Description: The missense mutation p.F877L (. in gene AR cause the resistance of Apalutamide by aberration of the drug's therapeutic target

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3) [42]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PNT1A cells; Prostate; Homo sapiens (Human); CVCL_2163
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [21]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3) [42]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [22]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3) [42]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PC-3 cells; Bone; Homo sapiens (Human); CVCL_0035
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [23]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Key Molecule: Homeodomain-interacting protein kinase 3 (HIPK3) [42]

• Metabolic Type: Mitochondrial metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Apalutamide
• Molecule Alteration: .; .
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Drug Resistance: Apoptosis rate assay
• Mechanism Description: Recently, we have demonstrated that an inhibitor of the mitochondrial electron transport chain complex I IACS-010759 ('IACS') acts synergistically with ARN in reducing PCa cell growth [24]. In this study, we investigated the effects of ARN and IACS on the mitochondrial network architecture and dynamics in PCa cells. Additionally, we explored the effect of androgen in regulating the mitochondrial network dynamics and metabolic modulations of respiratory pathways.

Cloperastine

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Calcium/calmodulin-dependent protein kinase type II subunit delta (CAMK2D) [45]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Cloperastine
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Oxytocin signaling pathway; Activation; hsa04921
• In Vitro Model: DU145CR cells; prostate; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: MS analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. We identified the OXT-signaling pathway as a potential target for CBZ-resistant CRPC using single-cell transcriptomic analysis of CTCs. CLO may potentially overcome CBZ resistance in CRPC by inhibiting the OXT-signaling pathway.

Clinical Trial Drug(s) 4 drug(s) in total

Canertinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protransforming growth factor alpha (TGFA) [2]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Canertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.36E-10; Fold-change: 1.90E-01; Z-score: 6.41E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.

Key Molecule: Proepiregulin (EREG) [2]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Canertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.31E-11; Fold-change: 7.13E-01; Z-score: 6.92E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.

Key Molecule: Amphiregulin (AREG) [2]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Canertinib
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.00E-02; Fold-change: 1.62E-01; Z-score: 2.30E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.

Trichostatin A

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Endoplasmic reticulum chaperone BiP (HSPA5) [18]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Trichostatin A
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 3.92E-01; Fold-change: 1.27E-02; Z-score: 8.69E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Inhibition; hsa04210
• In Vitro Model: C4-2B cells; Prostate; Homo sapiens (Human); CVCL_4784
• Experiment for Molecule Alteration: Western blot 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.

Camptothecin

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: NAD-dependent protein deacetylase sirtuin-1 (SIRT1) [23]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Camptothecin
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.32E-01; Fold-change: -1.01E-02; Z-score: -3.46E-01
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell apoptosis; Activation; hsa04210
• Cell Pathway Regulation: Cell growth; Inhibition; hsa05200
• Cell Pathway Regulation: Cell proliferation; Inhibition; hsa05200
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: PrEC cells; Prostate; Homo sapiens (Human); CVCL_0061
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Trypan blue dye exclusion assay
• Mechanism Description: Inhibition of the SIRT1 activity or expression resulted in attenuation of cell proliferation and chemoresistance in PC3 and DU145 cells. Ectopic expression of miR-34a decreased the SIRT1 mRNA and protein levels as well as protein levels of known direct target genes. Ectopic miR-34a expression resulted in cell cycle arrest and growth inhibition and attenuated chemoresistance to anticancer drug camptothecin by inducing apoptosis.

Genistein

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: HOX transcript antisense RNA (HOTAIR) [34]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Genistein
• Molecule Alteration: Expression; Down-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate adenocarcinoma
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.52E-06; Fold-change: -2.11E+00; Z-score: -5.01E+00
• 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: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• In Vitro Model: PC3 cells; Prostate; Homo sapiens (Human); CVCL_0035
• In Vitro Model: RWPE-1 cells; Prostate; Homo sapiens (Human); CVCL_3791
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: MTS assay
• Mechanism Description: Knockdown (siRNA) of HOTAIR decreased PCa cell proliferation, migration and invasion and induced apoptosis and cell cycle arrest. miR-34a was also up-regulated by genistein and may directly target HOTAIR in both PC3 and DU145 PCa cells.

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

Tyrphostin AG-1478

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protransforming growth factor alpha (TGFA) [2]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Tyrphostin AG-1478
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 8.36E-10; Fold-change: 1.90E-01; Z-score: 6.41E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.

Key Molecule: Proepiregulin (EREG) [2]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Tyrphostin AG-1478
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 7.31E-11; Fold-change: 7.13E-01; Z-score: 6.92E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.

Key Molecule: Amphiregulin (AREG) [2]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Sensitive Drug: Tyrphostin AG-1478
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Blood
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.10E-17; Fold-change: 3.99E-01; Z-score: 9.35E+00
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Cell migration; Activation; hsa04670
• Cell Pathway Regulation: Cell proliferation; Activation; hsa05200
• Cell Pathway Regulation: EGFR/RAS signaling pathway; Activation; hsa01521
• In Vitro Model: DU-145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• In Vivo Model: Nude mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Promega assay
• Mechanism Description: The induction of bone metastasis and TkI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands (EREG and TGFA) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TkIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature.

Gardiquimod

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

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

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Resistant Drug: Gardiquimod
• Molecule Alteration: Expression; Up-regulation

Differential expression of the molecule in resistant disease

• Classification of Disease: Prostate cancer [ICD-11: 2C82]
• The Specified Disease: Prostate cancer
• The Studied Tissue: Prostate
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 2.55E-01; Fold-change: 5.35E-02; Z-score: 1.16E+00
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Hep3B cells; Liver; Homo sapiens (Human); CVCL_0326
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Resazurin Cell Viability Assay
• Mechanism Description: Imidazoquinolines IMQ, RSQ, and GDQ are substrates for P-gp and begins to elucidate differences in their trafficking in cancer cells as a consequence of acquired drug resistance. We believe this work that begins to examine imidazoquinoline trafficking will prove useful in the future rational design of immunotherapeutics with enhanced susceptibility to P-gp efflux that enable increased bioavailability, in MDR cancers.

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