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

Author

Listed:
  • 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
    University of California San Francisco)

  • Rahul Aggarwal

    (University of California San Francisco
    University of California San Francisco)

  • David A. Quigley

    (University of California San Francisco
    University of California San Francisco)

  • Jack F. Youngren

    (University of California San Francisco
    University of California San Francisco)

  • Charles J. Ryan

    (University of Minnesota)

  • Martin Gleave

    (University of British Columbia)

  • Yuzhuo Wang

    (University of British Columbia
    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
    VA Greater Los Angeles Healthcare System)

  • 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
    University of California San Francisco)

  • Eric J. Small

    (University of California San Francisco
    University of California San Francisco)

  • Joel A. Yates

    (University of Michigan)

  • Zheng Xia

    (Oregon Health & Science University)

  • Joshi J. Alumkal

    (University of Michigan)

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.

Suggested Citation

  • 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 & Rah, 2022. "Transcriptional profiling of matched patient biopsies clarifies molecular determinants of enzalutamide-induced lineage plasticity," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-32701-6
    DOI: 10.1038/s41467-022-32701-6
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