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 ColemanColm 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

Research output: Contribution to journalArticlepeer-review

12 Scopus citations

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.

Original languageEnglish (US)
Article number5345
JournalNature communications
Volume13
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
This research was supported by the Stand Up to Cancer-Prostate Cancer Foundation (PCF) Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409 (T.M.B., R.A., D.A.Q., C.J.R., M.G., J.H., C.P.E., P.L., R.E.R., O.W., M.R., J.M.S., G.V.T., F.Y.F., E.J.S., J.J.A.) and a Prostate Cancer Foundation Challenge Award (J.J.A.). Other support includes: National Cancer Institute (NCI) R01 CA251245 (J.J.A.), R01 CA234715 (PSN); The Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE) NCI P50 CA097186 (M.C.H., C.M., P.S.N., J.J.A.); the Michigan Prostate SPORE NCI P50 CA186786 (AMU, J.J.A.); NCI P01 CA163227 (PSN); The Drug Resistance and Sensitivity Network NCI U54 CA224079 (PSN) and NCI P50 CA186786-07S1 (J.J.A.); NCI T32 CA009357 (T.C.W.); University of Michigan Rogel Cancer Center Innovation Award NCI P30 CA046592 (J.J.A.); Department of Defense Idea Award (W81XWH-20-1-0405) (J.J.A.); Department of Defense Idea Award (W81XWH2110539) (Z.X.); Grant 2021184 from the Doris Duke Charitable Foundation (M.C.H.); the V Foundation (MCH); National Comprehensive Cancer Network (NCCN)/Astellas Pharma Global Development Award (J.J.A.); the Sheppard Family Fund (J.J.A.). We would like to thank the staff of the Rogel Cancer Center Liquid Biopsy Shared Resource for technical expertise in isolation and molecular profiling of plasma cell-free DNA

Publisher Copyright:
© 2022, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, N.I.H., Extramural

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