Drug Information

Drug (ID: DG00247) and It's Reported Resistant Information

• Name: Enzalutamide
• Synonyms: MDV3100; Enzalutamide (AR inhibitor)
• Indication:
  In total 1 Indication(s)
  Prostate cancer [ICD-11: 2C82]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Prostate cancer [ICD-11: 2C82]; [1]
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Prostate cancer [ICD-11: 2C82]; [2]
• Target: Androgen receptor (AR); ANDR_HUMAN; [1]
• Formula: C21H16F4N4O2S
• IsoSMILES: CC1(C(=O)N(C(=S)N1C2=CC(=C(C=C2)C(=O)NC)F)C3=CC(=C(C=C3)C#N)C(F)(F)F)C
• InChI: 1S/C21H16F4N4O2S/c1-20(2)18(31)28(12-5-4-11(10-26)15(8-12)21(23,24)25)19(32)29(20)13-6-7-14(16(22)9-13)17(30)27-3/h4-9H,1-3H3,(H,27,30)
• InChIKey: WXCXUHSOUPDCQV-UHFFFAOYSA-N
• PubChem CID: 15951529
• ChEBI ID: CHEBI:68534
• TTD Drug ID: D0QK5X
• INTEDE ID: DR0583
• DrugBank ID: DB08899

Type(s) of Resistant Mechanism of This Drug

  ADTT: Aberration of the Drug's Therapeutic Target

  MRAP: Metabolic Reprogramming via Altered Pathways

  RTDM: Regulation by the Disease Microenvironment

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-02: Benign/in-situ/malignant neoplasm

Prostate cancer [ICD-11: 2C82]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Androgen receptor (AR) [1]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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) [1]

• Resistant Disease: Primary prostate cancer [ICD-11: 2C82.Z]
• 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.

Metabolic Reprogramming via Altered Pathways (MRAP)

Key Molecule: Solute carrier family 25 member 17 (SLC25A17) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Mechanistically, silencing of SLC25A17 and SLC27A6 led to the downregulation of FASN and ACC and their downstream metabolic products including triglycerides and lactic acid with a decrease in cell proliferation and migration in C4-2B enzalutamide resistant cells (Figures 5 and 6). Suppression of SLC25A17 and SLC27A6 delays cell cycle progression with the reduction in the protein expression of CyclinD1 and CDK6 in enzalutamide resistant cells (Figures 4 and 5).

Key Molecule: Solute carrier family 27 member 6 (SLC27A6) [2]

• Metabolic Type: Lipid metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Mechanistically, silencing of SLC25A17 and SLC27A6 led to the downregulation of FASN and ACC and their downstream metabolic products including triglycerides and lactic acid with a decrease in cell proliferation and migration in C4-2B enzalutamide resistant cells (Figures 5 and 6). Suppression of SLC25A17 and SLC27A6 delays cell cycle progression with the reduction in the protein expression of CyclinD1 and CDK6 in enzalutamide resistant cells (Figures 4 and 5).

Key Molecule: Chromosome 3 open reading frame 14 (C3orf14) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-11B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Chromosome 3 open reading frame 14 (C3orf14) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-2B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Family with sequence similarity 92 member A (FAM92A) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-16B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Family with sequence similarity 92 member A (FAM92A) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-7B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Histone cluster 1 H1 family member d (HIST1H1D) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-12B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Histone cluster 1 H1 family member d (HIST1H1D) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-3B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Podoplanin (PDPN) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-18B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Podoplanin (PDPN) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-9B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-17B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-8B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Homeobox D10 (HOXD10) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-13B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Homeobox D10 (HOXD10) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-4B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Homeobox D11 (HOXD11) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-14B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Homeobox D11 (HOXD11) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-5B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Homeobox D13 (HOXD13) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-15B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Homeobox D13 (HOXD13) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-6B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Ladybird homeobox 1 (LBX1) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-10B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

Key Molecule: Ladybird homeobox 1 (LBX1) [3]

• Metabolic Type: Glutamine metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• 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
• Experiment for Molecule Alteration: qRT-PCR
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: We compared the transcriptomic profile of paired enzalutamide-sensitive and resistant LNCaP and C4-19B prostate cancer cells for identification of genes involved in drug resistance by performing an unbiased bioinformatics analysis and further validation

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

• Metabolic Type: Glucose metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: Transcriptome datasets
• Experiment for Drug Resistance: Cell viability assay
• Mechanism Description: Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo.

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

• Metabolic Type: Glucose metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: PCa cells; Prostate; Homo sapiens (Human); CVCL_VF94
• Experiment for Molecule Alteration: Transcriptome datasets
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo.

Key Molecule: Mitochondrial pyruvate carrier (MPC) [5]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Nude (nu/nu) mice, with LNCaP cells; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: In this study, we demonstrate, for the first time, that MPC was significantly expressed at low levels in NEPC cells and that its downregulation contributed to NED and enzalutamide resistance. Moreover, MPC overexpression increased enzalutamide sensitivity and reversed NED in adenocarcinoma prostate cancer. These effects were likely mediated through the EMT induced by nuclear PKM2 translocation, which is controlled by acetyl-CoA, a product of pyruvate catabolism.

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

• Metabolic Type: Glucose metabolism
• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: Male BALB/c nude mice, overexpression of SLC4A4 in LNCaP cells; Mice
• Experiment for Molecule Alteration: Transcriptome datasets
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo.

Key Molecule: Small nucleolar RNA host gene 3 (SNHG3) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM2 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Key Molecule: microRNA-139-5p (miR-139-5p) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM3 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Key Molecule: Pyruvate kinase M2 (PKM) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vitro Model: C4-2 cells; Prostate; Homo sapiens (Human); CVCL_4782
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM4 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Key Molecule: Small nucleolar RNA host gene 3 (SNHG3) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vivo Model: 4-weeks-old male nude mice, with empty vector, sh-LncRNA SNHG3, sh-PKM2, sh-LncRNA SNHG3 + sh-PKM2 were separately injected; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM5 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Key Molecule: microRNA-139-5p (miR-139-5p) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vivo Model: 4-weeks-old male nude mice, with empty vector, sh-LncRNA SNHG3, sh-PKM2, sh-LncRNA SNHG3 + sh-PKM3 were separately injected; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM6 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Key Molecule: Pyruvate kinase M2 (PKM) [6]

• Metabolic Type: Glucose metabolism
• Resistant Disease: Castration-resistant prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Central carbon metabolism in cancer; Activation; hsa05230
• In Vivo Model: 4-weeks-old male nude mice, with empty vector, sh-LncRNA SNHG3, sh-PKM2, sh-LncRNA SNHG3 + sh-PKM4 were separately injected; Mice
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Tumor weight assay
• Mechanism Description: Mechanistic dissection demonstrated that lncRNA SNHG3 facilitated the advance of CRPC by adjusting the expression of PKM2. Further explorations unraveled the role of lncRNA SNHG3 as a 'sponge' of miR-139-5p and released its binding with PKM2 mRNA, leading to PKM2 up-regulation. Together, Our studies suggest that lncRNA SNHG3 / miR-139-5p / PKM7 pathway promotes the development of CRPC via regulating glycolysis process and provides valuable insight into a novel therapeutic approach for the disordered disease.

Regulation by the Disease Microenvironment (RTDM)

Key Molecule: Extracellular matrix protein 1 (ECM1) [7]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Western blot assay
• Experiment for Drug Resistance: CCK8 assay; Colony formation assay
• Mechanism Description: It is demonstrated that under ENZ treatment, osteoblasts in the bone microenvironment secrete increased levels of extracellular matrix protein 1 (ECM1), which affects surrounding prostate cancer cells, promoting tumor cell proliferation and anti-androgen resistance. Mechanistically, ECM1 interacts with the enolase 1 (ENO1) receptor on the prostate cancer cell membrane, leading to its phosphorylation at the Y189 site. This event further recruits adapter proteins including growth factor receptor-bound protein 2 (GRB2) and son of sevenless homolog 1 (SOS1), which activates the downstream mitogen-activated protein kinase (MAPK) signaling pathway to induce anti-androgen resistance. Furthermore, inhibiting ECM1 or utilizing the ENO1-targeting inhibitor phosphonoacetohydroxamate (PhAH) significantly restores tumor cell sensitivity to ENZ. Taken together, a potential mechanism is identified through which osteoblast-derived ECM1 drives resistance in bone metastatic prostate cancer under ENZ treatment.

Key Molecule: Pro-neuregulin-1, membrane-bound isoform (NRG1) [8]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: DU145-EnzR cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: CAFs significantly promoted cell growth and enzalutamide resistance of PC3-EnzR and DU145-EnzR cells through substantial increased secretion of NRG1 by CAFs. Co-culturing enzalutamide-resistant prostate cancer cells (PC3-EnzR and DU145-EnzR) with CAFs further enhanced enzalutamide resistance, as evidenced by elevated IC50 values. Inhibition of NRG1 in CAFs attenuated their impact on enzalutamide resistance, providing insight into the role of NRG1 in mediating the crosstalk between CAFs and prostate cancer in the context of enzalutamide resistance. This study elucidates the pivotal role of CAF-secreted NRG1 in promoting enzalutamide resistance in prostate cancer, providing valuable insights for developing targeted therapeutic strategies to overcome resistance in advanced prostate cancer.

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Epidermal growth factor receptor kinase substrate 8 (EPS8) [9]

• Resistant Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: Ras/p53/JAK/PI3K signaling pathway; Regulation; N.A.
• In Vitro Model: LNCaP Enz-R cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: CCK8 assay
• Mechanism Description: This study investigated the role of Eps8 in prostate cancer. The LNCaP cell line and enzalutamide-resistant LNCaP (LNCaP Enz-R) cell lines were utilized for the investigation. Overexpression of Eps8 was observed in the LNCaP Enz-R cells. Transfecting pCMV-EPS8 also increased the levels of epithelial-to-mesenchymal transition (EMT), cell proliferation, and cell viability in both cell lines. Conversely, knockdown of Eps8 expression decreased the levels of EMT, cell proliferation, and cell viability in both cell lines. Furthermore, EPS8-induced EMT activation could be reversed by suppressing the Ras/JAK/PI3K signaling pathway. In vivo animal study also confirmed the crucial role of Eps8 expression in prostate cancer progression.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Metabolic Reprogramming via Altered Pathways (MRAP)

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

• Metabolic Type: Glucose metabolism
• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vivo Model: SLC4A4 knockdown male BALB/c nude mice; STAT3 knockdown male BALB/c nude mice; Mice
• Experiment for Molecule Alteration: Transcriptome datasets
• Experiment for Drug Resistance: Tumor volume assay
• Mechanism Description: Long-term Enz treatment leads to the up-regulation of SLC4A4, which in turn mediates P53 lactylation via the NF-kappaB/STAT3/SLC4A4 axis, ultimately leading to the development of Enz resistance and progression of PCa. SLC4A4 knockdown overcomes Enz resistance both in vitro and in vivo.

Key Molecule: microRNA-99b-5p (miR-99b-5p) [10]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: MDA PCa 2b cells; Prostate; Homo sapiens (Human); CVCL_4748
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-10p overexpression results in suppressing nuclear translocation of

Key Molecule: microRNA-99b-5p (miR-99b-5p) [10]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• 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: Colony formation assay
• Mechanism Description: On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-5p overexpression results in suppressing nuclear translocation of

Key Molecule: microRNA-99b-5p (miR-99b-5p) [10]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: DU145 cells; Prostate; Homo sapiens (Human); CVCL_0105
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-6p overexpression results in suppressing nuclear translocation of

Key Molecule: microRNA-99b-5p (miR-99b-5p) [10]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: LNCaP cells; Prostate; Homo sapiens (Human); CVCL_0395
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-7p overexpression results in suppressing nuclear translocation of

Key Molecule: microRNA-99b-5p (miR-99b-5p) [10]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: 22Rv-1 cells; Prostate; Homo sapiens (Human); CVCL_1045
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-8p overexpression results in suppressing nuclear translocation of

Key Molecule: microRNA-99b-5p (miR-99b-5p) [10]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: HIF-1 signaling pathway; Activation; hsa04066
• Cell Pathway Regulation: VEGF signaling pathway; Activation; hsa04370
• In Vitro Model: C4-2B cells; Prostate; Homo sapiens (Human); CVCL_4784
• Experiment for Molecule Alteration: qRT-PCR; Western blot analysis
• Experiment for Drug Resistance: Colony formation assay
• Mechanism Description: On the other hand, overexpression of miR-99b-5p (i.e. via transfection of miR-99b-5p mimic) targets/inhibits AR, mTOR and SMARCD1 simultaneously and blocks the translocation of mTOR/AR/SMARCD1 complex from cytoplasm to nucleus, consequently suppressing cell proliferation/survival and enhancing the cell apoptosis in PCa (especially AA PCA and CRPC). Furthermore, miR-99b-9p overexpression results in suppressing nuclear translocation of

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Hyaluronan mediated motility receptor (HMMR) [11]

• Sensitive Disease: Prostate cancer [ICD-11: 2C82.0]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Discovered Using In-vivo Testing Model
• Cell Pathway Regulation: Downstream AR signaling pathway; Regulation; N.A.
• Experiment for Molecule Alteration: Western blot assay; qRT-PCR
• Experiment for Drug Resistance: Cell viability assay; Apoptosis assay
• Mechanism Description: Transient downregulation of HMMR using SMARTpool siRNA (siHMMR) markedly inhibited cell proliferation and induced apoptosis compared to control siRNA (siCON) in enzalutamide-sensitive LNCaP and enzalutamide-resistant MR49F cells. Additionally, siHMMR suppressed the colony-forming abilities of both LNCaP and MR49F cells, indicative of reduced survival ability.

References

• Ref 1: Clonal origin and spread of metastatic prostate cancer. Endocr Relat Cancer. 2016 Apr;23(4):R207-17. doi: 10.1530/ERC-16-0049. Epub 2016 Mar 21.
• Ref 2: Role of solute carrier transporters SLC25A17 and SLC27A6 in acquired resistance to enzalutamide in castration-resistant prostate cancer. Mol Carcinog. 2022 Apr;61(4):397-407.
• Ref 3: Metabolic Reprogramming and Predominance of Solute Carrier Genes during Acquired Enzalutamide Resistance in Prostate Cancer. Cells. 2020 Nov 24;9(12):2535.
• Ref 4: SLC4A4 is a novel driver of enzalutamide resistance in prostate cancer. Cancer Lett. 2024 Aug 10;597:217070.
• Ref 5: Reprogramming hormone-sensitive prostate cancer to a lethal neuroendocrine cancer lineage by mitochondrial pyruvate carrier (MPC). Mol Metab. 2022 May;59:101466.
• Ref 6: Glycolysis related lncRNA SNHG3 / miR-139-5p / PKM2 axis promotes castration-resistant prostate cancer (CRPC) development and enzalutamide resistance. Int J Biol Macromol. 2024 Mar;260(Pt 2):129635.
• Ref 7: Osteoblast-Derived ECM1 Promotes Anti-Androgen Resistance in Bone Metastatic Prostate Cancer. Adv Sci (Weinh). 2025 Jan;12(2):e2407662.
• Ref 8: NRG1 secreted by cancer-associated fibroblasts contributes to enzalutamide resistance in prostate cancer cells. Am J Cancer Res. 2024 Oct 15;14(10):4830-4840.
• Ref 9: Knockdown of EPS8 expression attenuates the proliferation of enzalutamide-resistant prostate cancer cells. Am J Cancer Res. 2024 Oct 15;14(10):4717-4730.
• Ref 10: Tumor suppressive miR-99b-5p as an epigenomic regulator mediating mTOR/AR/SMARCD1 signaling axis in aggressive prostate cancer. Front Oncol. 2023 Nov 7;13:1184186.
• Ref 11: Targeting hyaluronan-mediated motility receptor (HMMR) enhances response to androgen receptor signalling inhibitors in prostate cancer. Br J Cancer. 2023 Oct;129(8):1350-1361.