Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity

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 () and Joshi J. Alumkal ()
Additional contact information
Thomas C. Westbrook: University of Michigan
Xiangnan Guan: Oregon Health & Science University
Eva Rodansky: University of Michigan
Diana Flores: University of Michigan
Chia Jen Liu: University of Michigan
Aaron M. Udager: University of Michigan
Radhika A. Patel: Fred Hutchinson Cancer Research Center
Michael C. Haffner: Fred Hutchinson Cancer Research Center
Ya-Mei Hu: Oregon Health & Science University
Duanchen Sun: Oregon Health & Science University
Tomasz M. Beer: Oregon Health & Science University
Adam Foye: University of California San Francisco
Rahul Aggarwal: University of California San Francisco
David A. Quigley: University of California San Francisco
Jack F. Youngren: University of California San Francisco
Charles J. Ryan: University of Minnesota
Martin Gleave: University of British Columbia
Yuzhuo Wang: University of British Columbia
Jiaoti Huang: Duke University
Ilsa Coleman: Fred Hutchinson Cancer Research Center
Colm Morrissey: University of Washington
Peter S. Nelson: Fred Hutchinson Cancer Research Center
Christopher P. Evans: University of California Davis
Primo Lara: University of California Davis
Robert E. Reiter: University of California Los Angeles
Owen Witte: Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA
Matthew Rettig: University of California Los Angeles
Christopher K. Wong: University of California, Santa Cruz
Alana S. Weinstein: University of California, Santa Cruz
Vlado Uzunangelov: University of California, Santa Cruz
Josh M. Stuart: University of California, Santa Cruz
George V. Thomas: Oregon Health & Science University
Felix Y. Feng: University of California San Francisco
Eric J. Small: University of California San Francisco
Joel A. Yates: University of Michigan
Zheng Xia: Oregon Health & Science University
Joshi J. Alumkal: University of Michigan

Nature Communications, 2022, vol. 13, issue 1, 1-13

Abstract: Abstract 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.

Date: 2022
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32701-6

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DOI: 10.1038/s41467-022-32701-6

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