Prostate cancer (PC) incidence is predicted to reach around 2 million new cases by 2040. High fat diet and obesity are associated with the progression and mortality of PC. Palmitate is a common saturated fatty acid, it induces endoplasmic reticulum (ER) stress that activates the unfolded protein response (UPR). Failure to adapt to ER stress results in apoptosis to eliminate irreversibly damaged cells. Master regulator analysis found that Arid5a was a master regulator of saturated fat-induced cellular responses. We confirmed that exogenous palmitate activated ARID5a/UPR signaling, while further activation could induce apoptosis. In trying to determine the mechanism of ARID5a activation, we found that palmitate promoted the expression of dopamine receptors 2 and 3 (DRD2, DRD3) in prostate cancer cell lines. Since high diets have other deleterious effects, we tested the role of dopamine receptor antagonists (e.g. ONC201, prochlorperazine) and found them to serve as UPR activators, inducing apoptosis in ARCaPM and 22Rv1 cells. As our data showed that ARID5a expression could inhibit prostate-specific membrane antigen (PSMA), we next tested the role of dopamine receptor antagonists in sensitizing castrate resistant cells to androgen targeted therapy. Both castrate resistant cell lines (22Rv1 and ARCaPM) were found to be made sensitive to enzalutamide by dopamine inhibition, inhibiting cell proliferation and promoting apoptosis. These findings are especially compelling since dopamine receptor antagonist, prochlorperazine, is a commonly prescribed anti-nausea drug and ONC201 is currently in clinical trials meeting safety endpoints. Preclinical studies in mouse models of castrate resistant PC support the administration of such dopamine receptor antagonists with androgen targeted therapy to sensitize otherwise refractile tumors by the promotion of ER stress pathway, addressing a common adaptation mechanism employed by cancer cells.

Citation Format: Le Zhang, Sandrine Billet, Gabrielle Gonzales, Krizia Rohena-Rivera, Hayato Muranaka, Yeonjoo Lee, Sungyong You, Edwin M. Posadas, Neil A. Bhowmick. Dopamine receptor antagonists sensitize prostate cancer cells to androgen targeted therapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B022.