Background: Novel agents that inhibit the androgen receptor (AR), including abiraterone acetate and enzalutamide, have significantly prolonged life in many men with metastatic castration-resistant prostate cancer (mCRPC). However, after 1-2 years of therapy acquired resistance to these drugs is nearly universal. Therefore, identifying mechanisms of resistance and innovative therapies to treat enzalutamide-resistant disease represents a major unmet clinical need.
Methods: In this study, we developed four enzalutamide-resistant cell lines and analyzed each cell line by RNA-seq and phospho-proteomics to identify common pathways deregulated during disease progression to enzalutamide resistance. We manipulated p38 levels and activity in order to determine its mechanistic relationship to resistance. We measured p38 activity in metastatic biopsies from men with both hormone-sensitive and metastatic prostate cancer.
Results: At the nexus of acquired enzalutamide resistance in four independently derived prostate cancer model systems, we identified a convergent mechanism of resistance through activation of the p38 stress response/dormancy pathway. Enzalutamide-resistant cells are sensitized to p38 inhibition, and enzalutamide- sensitive cells developed resistance to enzalutamide with constitutive activation of p38 signaling. Enzalutamide-resistant cells have sustained AR activity, which is blocked with genetic or small-molecule p38 inhibition, indicating that p38 promotes AR activity in the absence of ligand binding. Finally, we found common activation of p38 in lymph node, visceral, and bone metastases from men with mCRPC.
Conclusions: We have identified the stress response/dormancy p38-signaling pathway as a common mechanism driving enzalutamide resistance. Most importantly, p38 is a targetable pathway activated in tumors from men with mCRPC, suggesting that novel therapeutic strategies could be applied to prolong the lives of men with metastatic, drug-resistant prostate cancer.
Citation Format: Kathryn E. Ware, Santosh Gupta, Jared Eng, Wen-Chi Foo, Lorin Crawford, Garland Austin, Bhairavy Puviindran, Jennifer Freedman, Steven R. Patierno, Tian Zhang, David Corcoran, Mariaelena Pierobon, Emanuel Petricoin, Jason A. Somarelli, Andrew J. Armstong. Convergent hormone therapy resistance mediated by stress/dormancy-like pathways in prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B038.