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Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer.

ABSTRACT: After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the ligand-binding domain may mediate resistance to abiraterone and enzalutamide. Steroid receptors such as glucocorticoid receptor may substitute for AR. Drugs with novel mechanisms of action or combination therapy, along with biomarkers for patient selection, may be needed to improve the therapy of castration resistant prostate cancer.

SUBMITTER: Chism DD

PROVIDER: S-EPMC4221359 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Mechanisms of acquired resistance to androgen receptor targeting drugs in castration-resistant prostate cancer.

Chism David D DD De Silva Dinuka D Whang Young E YE

Expert review of anticancer therapy 20140613 11

After initial response to androgen receptor (AR) targeting drugs abiraterone or enzalutamide, most patients develop progressive disease and therefore, castration resistant prostate cancer remains a terminal disease. Multiple mechanisms underlying acquired resistance have been postulated. Intratumoral androgen synthesis may resume after abiraterone treatment. A point mutation in the ligand-binding domain of AR may confer resistance to enzalutamide. Emergence of AR splice variants lacking the liga ...[more]

PMID: 24927631

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Androgen receptor targeting drugs in castration-resistant prostate cancer and mechanisms of resistance.

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Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in Castration-Resistant Prostate Cancer

Project description:Illumina gene array analyses of prostate cancer cell lines that had acquired resistance to Enzalutamide (MDV3100). mRNA analyses of four cell lines (CWR-R1, LAPC-4, LNCaP, and VCAP) cells that were either untreated, treated for 48hrs with Enz (short-term), or continuously grown in Enzalutamide for >6 months.

2016-02-24 | E-GEOD-78201 | biostudies-arrayexpress

Targeting constitutively active androgen receptor splice variants in castration resistant prostate cancer.

Project description: Not available

| S-EPMC4975933 | biostudies-literature

Acquired Resistance to the Second-Generation Androgen Receptor Antagonist Enzalutamide in Castration-Resistant Prostate Cancer

Project description:Illumina gene array analyses of prostate cancer cell lines that had acquired resistance to Enzalutamide (MDV3100).

2016-02-24 | GSE78201 | GEO

Glucocorticoid receptor and androgen receptor-targeting therapy in patients with castration-resistant prostate cancer.

Project description:ObjectiveThe glucocorticoid receptor (GR) promotes resistance to androgen receptor (AR)-targeting therapies in castration-resistant prostate cancer (CRPC) by bypassing AR blockade. However, the clinical relevance of evaluating GR expression in patients with CRPC has not been determined. The present study investigated the association of relative GR expression in CRPC tissue samples with treatment response to AR-targeting therapy.MethodsLevels of GR, AR-FL, and AR-V7 mRNAs were measured in prostate cancer tissue from prospectively enrolled CRPC patients who were starting treatment. Patients were divided into groups with high and low AR-V7/AR-FL ratios and with high and low GR/AR-FL ratios. The primary endpoint was prostate-specific antigen (PSA) response rate to treatment.ResultsEvaluation of 38 patients treated with AR-targeting therapies showed that the PSA response rate was significantly higher in patients with low than high AR-V7/AR-FL ratios (77.8% vs. 25.0%, p=0.003) and in patients with low than high GR/AR-FL ratios (81.3% vs. 27.3%, p=0.003). Patients with low GR/AR-FL ratios had higher rates of PSA progression-free survival (46.0% vs. 22.4%, p=0.006), radiologic progression-free survival (28.9% vs. 10.0%, p=0.02), and overall survival (75.2% vs. 48.0%, p=0.037) than patients with high GR/AR-FL ratios. The association of GR/AR-FL ratio with PSA response to AR-targeting therapy remained significant in multivariable models. Evaluation of the 14 patients who received taxane chemotherapy showed that PSA response rates did not differ significantly in those with low and high AR-V7/AR-FL and GR/AR-FL ratios, although no definitive conclusions can be drawn due to the small number of patients.ConclusionRelative GR expression is associated with sensitivity to AR-targeting therapy and survival in patients with CRPC. Large-scale prospective validation and liquid biopsy-based studies are warranted.

| S-EPMC9541428 | biostudies-literature

Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer.

Project description:The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration-resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed that a novel class of agents (thailanstatins, TSTs and spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application.

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