The androgen receptor (AR) signaling inhibitor enzalutamide (enza) is one of the principal treatments for metastatic castration-resistant prostate cancer (CRPC). Several emergent enza clinical resistance mechanisms have been described, including lineage plasticity in which the tumors manifest reduced dependency on the AR. To improve our understanding of enza resistance, herein we analyze the transcriptomes of matched biopsies from men with metastatic CRPC obtained prior to treatment and at progression (n = 21). RNA-sequencing analysis demonstrates that enza does not induce marked, sustained changes in the tumor transcriptome in most patients. However, three patients' progression biopsies show evidence of lineage plasticity. The transcription factor E2F1 and pathways linked to tumor stemness are highly activated in baseline biopsies from patients whose tumors undergo lineage plasticity. We find a gene signature enriched in these baseline biopsies that is strongly associated with poor survival in independent patient cohorts and with risk of castration-induced lineage plasticity in patient-derived xenograft models, suggesting that tumors harboring this gene expression program may be at particular risk for resistance mediated by lineage plasticity and poor outcomes.
Nature communications. 2022 Sep 15*** epublish ***
Thomas C Westbrook, Xiangnan Guan, Eva Rodansky, Diana Flores, Chia Jen Liu, Aaron M Udager, Radhika A Patel, Michael C Haffner, Ya-Mei Hu, Duanchen Sun, Tomasz M Beer, Adam Foye, Rahul Aggarwal, David A Quigley, Jack F Youngren, Charles J Ryan, Martin Gleave, Yuzhuo Wang, Jiaoti Huang, Ilsa Coleman, Colm Morrissey, Peter S Nelson, Christopher P Evans, Primo Lara, Robert E Reiter, Owen Witte, Matthew Rettig, Christopher K Wong, Alana S Weinstein, Vlado Uzunangelov, Josh M Stuart, George V Thomas, Felix Y Feng, Eric J Small, Joel A Yates, Zheng Xia, Joshi J Alumkal
Division of Hematology and Oncology, Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA., Department of Pathology, Michigan Center for Translational Pathology, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA., Masonic Cancer Center, University of Minnesota; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA., Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada., Duke University, Durham, NC, USA., Department of Urology, University of Washington, Seattle, WA, USA., University of California Davis, Davis, CA, USA., University of California Los Angeles, Los Angeles, CA, USA., Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, Los Angeles, CA, USA., UC Santa Cruz Genomics Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA., Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. ., Division of Hematology and Oncology, Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. .