Abstract 3036: Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic anti-cancer effects in AR-V7-expressing mCRPC preclinical models

Abstract There is an unmet need to develop novel treatment options for patients with metastatic castration-resistant prostate cancer (mCRPC). Patients often develop resistance to hormonal therapies that target the AR-axis (e.g., abiraterone, enzalutamide). A splice variant of AR, AR-V7, is associated with resistance to these inhibitors as well as mCRPC progression and poor prognoses. We embarked upon a high-throughput screen to identify synergistic combinations of targeted therapies using two CRPC cell lines, LNCaP95 and VCaP-CR. The goal of the drug screen is to identify rational targeted combination therapies for mCRPC, where efficacy can be achieved at lower, equally effective doses in order to minimize toxicity. Extensive bioinformatic analysis identified several synergistic combinations, including dual targeting of Bcl-2 family proteins using BH3 mimetics. Combinations targeting Bcl-xL (A-1331852 and Navitoclax) and Mcl-1 (S63845) synergistically decreased cell viability and induced apoptotic activity via cleavage of PARP, caspase 3, and caspase 7 across AR-V7 expressing CRPC cell lines (LNCaP95, VCaP-CR, 22Rv1) as early as two hours post-treatment. The effect of the treatment combination on downstream targets was assessed via western blot analysis. We demonstrated synergistic anti-tumor effects with Mcl-1/Bcl-xL co-targeting in three-dimensional (3D) spheroid CRPC models and in the patient-derived LuCaP-167CR organoid model, which represents a more physiologically relevant model for evaluating drug response and efficacy. We also explored the use of a Bcl-xL-specific PROTAC to minimize platelet toxicity associated with Bcl-xL inhibitors in the clinic. We showed similar synergistic efficacy with the S63845/Bcl-xL targeting PROTAC combination in the 3D spheroid models compared to the small-molecule Bcl-xL inhibitors while also inducing apoptosis. Our findings provide unique insight into the dependence on Bcl-2 family proteins in mCRPC. Our findings also support further preclinical development of Bcl-xL and Mcl-1 inhibitors for mCRPC. Citation Format: Benjamin C. Brim Andres F. Leon Erica L. Beatson Jessica D. Kindrick Kinjal Bhadresha Xiaohu Zhang Giulia C. Napoli Emily N. Risdon Keith T. Schmidt Erin Beck Carleen Klumpp-Thomas Michele Cerebelli Douglas K. Price Cindy H. Chau Craig J. Thomas William D. Figg. Direct co-targeting of Bcl-xL and Mcl-1 exhibits synergistic anti-cancer effects in AR-V7-expressing mCRPC preclinical models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3036.