Linking prostate cancer cell AR heterogeneity to distinct castration and enzalutamide responses

Abstract

Expression of androgen receptor (AR) in prostate cancer (PCa) is heterogeneous but the functional significance of AR heterogeneity remains unclear. Screening ~200 castration-resistant PCa (CRPC) cores and whole-mount sections (from 89 patients) reveals 3 AR expression patterns: nuclear (nuc-AR), mixed nuclear/cytoplasmic (nuc/cyto-AR), and low/no expression (AR−/lo). Xenograft modeling demonstrates that AR+ CRPC is enzalutamide-sensitive but AR−/lo CRPC is resistant. Genome editing-derived AR+ and AR-knockout LNCaP cell clones exhibit distinct biological and tumorigenic properties and contrasting responses to enzalutamide. RNA-Seq and biochemical analyses, coupled with experimental combinatorial therapy, identify BCL-2 as a critical therapeutic target and provide proof-of-concept therapeutic regimens for both AR+/hi and AR−/lo CRPC. Our study links AR expression heterogeneity to distinct castration/enzalutamide responses and has important implications in understanding the cellular basis of prostate tumor responses to AR-targeting therapies and in facilitating development of novel therapeutics to target AR−/lo PCa cells/clones.

Dysregulated Alternative Splicing Landscape Identifies Intron Retention as a Hallmark and Spliceosome as a Therapeutic Vulnerability in Aggressive Prostate Cancer

“…S13B). Since the LAPC9-AI has the AR −/lo phenotype (36), transcription of AR signaling, as expected, remained unaltered (Supplementary Fig. S13C).…”

“…To evaluate the activity of E7107 against CRPC in vivo , we treated 3 distinct castration-resistant (AI) PCa xenograft models, i.e., the AR +/hi LNCaP-AI (36), AR −/lo LAPC9-AI (36) and AR − PC3, with E7107 or vehicle (Fig. 7A).…”

“…7A). The LNCaP-AI and LAPC9-AI models were established by serially passaging the corresponding parent AD tumor cells in castrated immunodeficient mice (36). The LNCaP-AI was initially responsive to Enza but quickly became Enza-resistant whereas LAPC9-AI was refractory to Enza de novo (36).…”

“…The LNCaP-AI and LAPC9-AI models were established by serially passaging the corresponding parent AD tumor cells in castrated immunodeficient mice (36). The LNCaP-AI was initially responsive to Enza but quickly became Enza-resistant whereas LAPC9-AI was refractory to Enza de novo (36). Treatment of Enza-refractory LAPC9-AI tumors with either one cycle (i.e., tail vein injection for 5 consecutive days) or two cycles (with 1 week of ‘drug holiday’ between the 2 cycles) effectively inhibited tumor growth (Fig.…”

Incidence of androgen receptor and androgen receptor variant 7 coexpression in prostate cancer

“…While it is generally accepted that there are cell populations within the normal prostate that do not express AR, 37 this AR-low cell population in the later stages of PRCA progression may be of interest in terms of antiandrogen therapy resistance. 39 This concept of AR heterogeneity has previously been associated with poor outcomes in patient survival, and this study provides evidence that these cell populations are present in human PRCA. 33,34 Finally, this study showed an increase of ARv7 in metastatic PRCA, as expected.…”