Abstract 4302: ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer

Abstract

Abstract Androgen receptor- (AR-) indifference is a mechanism of resistance to hormonal therapy in prostate cancer (PC). Here we demonstrate that ONECUT2 (OC2) activates resistance through multiple drivers associated with adenocarcinoma, stem-like and neuroendocrine (NE) variants. Direct OC2 targets include the glucocorticoid receptor (GR) and the NE splicing factor SRRM4, which are key drivers of lineage plasticity. Thus, OC2, despite its previously described NEPC driver function, can indirectly activate a portion of the AR cistrome through epigenetic activation of GR. Mechanisms by which OC2 regulates gene expression include promoter binding, enhancement of genome-wide chromatin accessibility, and super-enhancer reprogramming. Pharmacologic inhibition of OC2 suppresses lineage plasticity reprogramming induced by the AR signaling inhibitor enzalutamide. These results demonstrate that OC2 activation promotes a range of drug resistance mechanisms associated with treatment-emergent lineage variation in PC and support enhanced efforts to therapeutically target OC2 as a means of suppressing treatment-resistant disease. Citation Format: Chen Qian, Qian Yang, Mirja Rotinen, Rongrong Huang, Hyoyoung Kim, Brad Gallent, Yiwu Yan, Radu M. Cadaneanu, Baohui Zhang, Salma Kaochar, Stephen J. Freedland, Edwin M. Posadas, Leigh Ellis, Dolores Di Vizio, Colm Morrissey, Peter S. Nelson, Lauren Brady, Ramachandran Murali, Moray J. Campbell, Wei Yang, Beatrice S. Knudsen, Elahe A. Mostaghel, Huihui Ye, Isla P. Garraway, Sungyong You, Michael R. Freeman. ONECUT2 activates diverse resistance drivers of androgen receptor-independent heterogeneity in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4302.