Quevedo, Jorge F

Abstract Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3′ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31–12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704–15. ©2017 AACR.

Objectives To evaluate the prognostic significance of germline variation in candidate genes in patients with castration‐resistant prostate cancer (CRPC). Methods Germline DNA was extracted from peripheral blood mononuclear cells of patients with CRPC enrolled in a clinically annotated registry. Fourteen candidate genes implicated in either initiation or progression of prostate cancer were tagged using single nucleotide polymorphisms (SNPs) from HapMap with a minor allele frequency of >5%. The primary endpoint was overall survival (OS), defined as time from development of CRPC to death. Principal component analysis was used for gene levels tests of significance. For SNP‐level results the per allele hazard ratios (HRs) and 95% confidence intervals (CIs) under the additive allele model were estimated using Cox regression, adjusted for age at CRPC and Gleason score (GS). Results A total of 240 patients with CRPC were genotyped (14 genes; 84 SNPs). The median (range) age of the cohort was 69 (43–93) years. The GS distribution was 55% with GS ≥8, 32% with GS = 7 and 13% with GS <7 or unknown. The median (interquartile range) time from castration resistance to death for the cohort was 2.67 (1.6–4.07) years (144 deaths). At the gene level, a single gene, JAK2 was associated with OS ( P < 0.01), and 11 of 18 JAK2 SNPs were individually associated with OS after adjustment for age and GS. A multivariate model consisting of age, GS, rs2149556 (HR 0.67; 95% CI 0.38–1.18) and rs4372063 (HR 2.17; 95% CI 1.25–3.76) was constructed to predict survival in patients with CRPC (concordance of 0.69, P < 3.2 × 10 −9 ). Conclusions Germline variation in the JAK2 gene was associated with survival in patients with CRPC and warrants further validation as a potential prognostic biomarker.