Authors:

Brett Andrew Anderson

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About Paper:

According to the American Cancer Society, prostate cancer (PCa) is the second-leading cause of cancer- related deaths in American men. Although androgen deprivation therapy (ADT) is effective at lowering the morbidity rate, later stages of this disease will stop responding to ADT and develop into castration-resistant prostate cancer (CRPC). The progression from PCa to CRPC is marked by changes to androgen receptor (AR) target gene expression, wherein AR-target genes, regardless of therapeutic intervention, are independently altered to prevent programmed cell death and allow for uninhibited proliferation. This functional transition is exemplified in CRPC patients who may show near castrate-levels of androgens, but intratumoral androgen levels still remain very high. Our lab recently found that the SWI/SNF chromatin remodeling complex known as GBAF (GLTSCR1/like-containing BRG1/BRM-Associated Factors) is an important regulator of AR-target gene expression and cell viability in CRPC cell models. One GBAF complex subunit, BRD9 (bromodomain containing 9), decreases AR-target gene transcription when pharmacologically inhibited. Given that frontline therapies for CRPC, such as enzalutamide (ENZA), inhibit AR binding in the nucleus, functional inhibition of GBAF via BRD9 degraders may potentiate this mechanism. The purpose of this study was to characterize PCa cell line responses to combination treatment of ENZA and the BRD9 degrader VZ-185. Our results demonstrate that functional inhibition of the GBAF complex via BRD9 degradation enhances the effect of ENZA on CRPC cell models, which suggests that BRD9 may be a potential therapeutic target for future animal studies regarding CRPC treatment. Keywords: Prostate Cancer; Androgen Receptor; GBAF; BRD9; Enzalutamide

Source:

Purdue University / 2024

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Co-authors:

Brett Andrew Anderson