Systemic targeted therapy in prostate cancer is primarily focused on ablating androgen signaling. Androgen deprivation therapy and second-generation androgen receptor (AR)-targeted therapy selectively favor the development of treatment-resistant subtypes of metastatic castration-resistant prostate cancer (mCRPC), defined by AR and neuroendocrine (NE) markers. Molecular drivers of double-negative (AR-/NE-) mCRPC are poorly defined. In this study, we comprehensively characterized treatment-emergent mCRPC by integrating matched RNA sequencing, whole-genome sequencing, and whole-genome bisulfite sequencing from 210 tumors. AR-/NE- tumors were clinically and molecularly distinct from other mCRPC subtypes, with the shortest survival, amplification of the chromatin remodeler CHD7, and PTEN loss. Methylation changes in CHD7 candidate enhancers were linked to elevated CHD7 expression in AR-/NE+ tumors. Genome-wide methylation analysis nominated KLF5 as a driver of the AR-/NE- phenotype, and KLF5 activity was linked to RB1 loss. These observations reveal the aggressiveness of AR-/NE- mCRPC and could facilitate the identification of therapeutic targets in this highly aggressive disease.
Cancer research. 2023 Jun 08 [Epub ahead of print]
Arian Lundberg, Meng Zhang, Rahul 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, Rob E Reiter, Matthew B Rettig, Owen N Witte, Alexander W Wyatt, Felix Y Feng, Eric J Small, David A Quigley
University of California San Francisco Medical Center, San Francisco, CA, United States., University of California, San Francisco, San Francisco, United States., University of California, San Francisco, San Francisco, CA, United States., University of California - San Francisco School of Medicine, San Francisco, CA, United States., University of California, San Francisco, San Franciso, United States., University of California, San Francisco, United States., University of Michigan Medical School, Ann Arbor, MI, United States., Exact Sciences (United States), Madison, WI, United States., BC Cancer, Vancouver, British Columbia, Canada., University of California, Davis, Sacramento, CA, United States., University of British Columbia, Vancouver, BC, Canada., University of California Davis Medical Center, Sacramento, California, United States., University of California, Los Angeles, Los Angeles, CA, United States., University of British Columbia, Vancouver, British Columbia, Canada., UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, United States.