Abstract LB411: Investigating the dependency of androgen receptor-positive prostate cancer on class I myosins

Abstract

Abstract Prostate adenocarcinoma is characterized by high expression and activity of the androgen receptor (AR). AR is a nuclear hormone receptor that stimulates anabolic cell metabolism. We hypothesized that the high activity of AR in prostate cancer creates unique dependencies on cellular machinery to support this high rate of anabolism. We observed that androgen treatment of patients with metastatic castration-resistant prostate cancer resulted in increased abundance of MYO1E, a class I myosin that facilitates intracellular vesicular trafficking, in tumor biopsies. Similarly, MYO1E protein increased in AR+ prostate cancer cell lines upon treatment with androgens. Notably, a specific small molecule inhibitor of MYO1E, pentachloropseudilin (PClP), induced cell death of AR-positive prostate cancer cell lines with an IC50 of 2-4uM, but was non-toxic to AR-negative prostate cancer cell lines. Expression of AR in these AR-negative lines conferred sensitivity to PClP, while deletion of AR in an AR-positive line conferred resistance to PClP, indicating that AR expression was required and sufficient for sensitivity of prostate cancer cell lines to PClP. Previous studies have suggested that AR globally increases protein synthesis and proteotoxic stress, and we asked whether this may create a dependency on MYO1E for secretion of protein-containing vesicles to manage proteotoxic stress. Initial experiments suggest that AR increases global rates of protein synthesis, as assessed by puromycin-incorporation assays, and inhibition of MYO1E increases phosphorylation of EIF2A, suggestive of activation of the integrated stress response. Further experiments will determine the essential function of MYO1E in AR-positive prostate cancer. Altogether our studies suggest that the class I myosin MYO1E is an essential protein in AR-positive cell lines and may represent a novel drug target for prostate adenocarcinoma. Citation Format: Anoushka Kadam, Shivani Kumar, Varsha Vakkala, Rajendra Kumar, Angelo M. De Marzo, Edward J. Pearce, Laura A. Sena. Investigating the dependency of androgen receptor-positive prostate cancer on class I myosins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB411.