Abstract
Abstract The androgen receptor (AR) signaling pathway plays a primary role in prostate cancer progression. Various types of androgen receptor antagonists including enzalutamide, abiraterone and apalutamide have been widely used as single agents to treat patients with advanced disease. However, despite the initial improvements, patients with metastatic castration-resistant prostate cancer (mCPRC) frequently develop resistance, resulting in limited overall survival benefit. Darolutamide is a novel next-generation androgen receptor-signaling inhibitor currently in phase III clinical trials and has shown efficacy and tolerability in treating non-metastatic castration-resistant prostate cancer. ONC201 is a small molecule belonging to the imipridone class that activates the integrated stress response (ISR) pathway and upregulates TRAIL. ONC201 has demonstrated promising antiproliferative and proapoptotic effects in a variety of tumor types and is currently being evaluated in phase I/II clinical trials. This study investigates the integrated stress response and androgen receptor signaling as mechanisms for antitumor efficacy with ONC201 and enzalutamide or darolutamide as single agents or in combination against mCRPC in vitro and in vivo. Three mCRPC cell lines 22RV1, LNCaP, and PC3 were treated with ONC201, darolutamide, and enzalutamide as single agents or in combinations. In 22RV1, the single agent IC50 was calculated to be 1.22uM for ONC201, 51.5uM for darolutamide and >80uM for enzalutamide. In LNCaP, the single agent IC50s are 1.67uM for ONC201, 58.7uM for darolutamide, and 4.05uM for enzalutamide. In 22RV1, the combination index (CI) of 0.38 was obtained when treated with 40uM of darolutamide and 1.25uM of ONC201, CI was 0.35 when treated with 80uM of enzalutamide and 1.25uM of ONC201. In LNCaP, CI of 0.19 was obtained when treated with 10uM of darolutamide and 0.3125uM of ONC201, CI was 0.45 when treated with 5uM of enzalutamide and 2uM of ONC201. Results showed that ONC201 synergized with darolutamide and enzalutamide and decreased cell viability. In both 22RV1 and LNCaP cell lines, when compared to single agents, combination treatments of ONC201 and darolutamide or enzalutamide reduced PSA level and demonstrated proapoptotic effects. Mouse xenograft models with luciferase expressing 22RV1 and LNCaP cell lines are currently being treated with ONC201 and darolutamide or enzalutamide as single agents or in combinations and the in vivo studies are ongoing. Our data provide insights to improved therapeutic benefits of combination treatment that can be further developed for more efficient anticancer strategies. Citation Format: Jinxuan Laura Wu, Lanlan Zhou, Leiqing Zhang, Kelsey E. Huntington, Benedito Carneiro, Wafik S. El-Deiry. Antitumor efficacy of combination treatment with ONC201 and enzalutamide or darolutamide in metastatic castration-resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3947.
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