Castration resistance prostate cancer (CRPC) first manifests as a sustained rise in the androgen-responsive gene, PSA, consistent with reactivation of a functioning androgen receptor (AR) axis. This observation led to the development of “second-line” therapies aimed at further blocking androgen/AR signaling. Unfortunately, resistance to these agents can also develop quickly. Paradoxically, several studies have suggested that the growth of AR-positive human CRPC cell lines may be inhibited by supraphysiologic levels of testosterone (SupT). These studies suggested that the adaptive reliance on AR signaling by CRPC cells becomes a therapeutic liability that can be exploited through the administration of SupT, which we termed as bipolar androgen therapy (BAT). Understanding how BAT works at the molecular and cellular levels might help in rationally combining BAT with other agents to achieve increased efficacy and tumor responses. Our data indicates that SupT induces DNA double strand breaks (DSBs) in prostate cancer (PCa) cells. Unrepaired DSBs induced by SupT are routed for specialized autophagic degradation, termed nucleophagy. We further show that SupT-induced autophagosomal DNA can activate cytoplasmic DNA sensing pathways and downstream innate immune signaling. Based on our findings, we propose that BAT engages the immune system to inhibit tumor growth. Future combination of BAT with existing immunotherapeutics including immune checkpoint blockade may prove beneficial for treatment of CRPC.

Citation Format: Janet Mendonca, Olutosin Owoyemi, Marc Rosen, Michael Carducci, Mark Markowski, Emmanuel Antonarakis, Drew Pardoll, Samuel Denmeade, Sushant K. Kachhap. Supraphysiological androgens activate innate immune signaling in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 517.