Abstract B012: Genomic and epigenomic drivers of double-negative metastatic prostate cancer

Abstract Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen receptor (AR) signaling. Androgen deprivation therapy and second-generation AR-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by whether the tumor expresses either AR or neuroendocrine (NE) markers. Among the subtypes of mCRPC, the molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterize genomic and epigenomic features of treatment-emergent mCRPC subtypes in 210 tumors by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing. We show that AR-/NE- tumors exhibit a clinically and molecularly distinct phenotype. Patients with AR-/NE- mCRPC tumors have the shortest survival, and these tumors preferentially harbor amplification of the chromatin remodeler CHD7 and loss of PTEN. We demonstrate that methylation changes in CHD7 candidate enhancers are linked to elevated CHD7 expression in AR-/NE+ tumors. Moreover, we use genome-wide methylation analysis to nominate the Krüppel-like factor gene KLF5 as a driver of the AR-/NE- phenotype and link its activity to loss of the tumor suppressor RB1. These observations reveal the aggressiveness of the AR-/NE- tumors and elucidate genomic and epigenomic drivers of mCRPC subtypes, which may facilitate the identification of novel therapeutic targets in this highly aggressive disease. Citation Format: Arian Lundberg, Meng Zhang, Rahul R. Aggarwal, Haolong Li, Li Zhang, Adam Foye, Martin Sjöström, Jonathan Chou, Kevin Chang, Thaidy Moreno-Rodriguez, Raunak Shrestha, Avi Baskin, Xiaolin Zhu, Alana S. Weinstein, Noah Younger, Joshi J. Alumkal, Tomasz M. Beer, Kim N. Chi, Christopher P. Evans, Martin Gleave, Primo N. Lara, Robert E. Reiter, Matthew B. Rettig, Owen N. Witte, Alexander W. Wyatt, Felix Y. Feng, Eric J. Small, David A. Quigley. Genomic and epigenomic drivers of double-negative metastatic prostate cancer [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 B012.