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; Joshi J Alumkal

doi:10.1038/s41467-022-32701-6

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

Nat Commun. 2022 Sep 15;13(1):5345. doi: 10.1038/s41467-022-32701-6.

Authors

Thomas C Westbrook^#¹, Xiangnan Guan^#², Eva Rodansky¹, Diana Flores¹, Chia Jen Liu³, Aaron M Udager³, Radhika A Patel⁴, Michael C Haffner⁴, Ya-Mei Hu², Duanchen Sun², Tomasz M Beer², Adam Foye^{5

6}, Rahul Aggarwal^{5

6}, David A Quigley^{5

6}, Jack F Youngren^{5

6}, Charles J Ryan⁷, Martin Gleave⁸, Yuzhuo Wang^{8

9}, Jiaoti Huang¹⁰, Ilsa Coleman⁴, Colm Morrissey¹¹, Peter S Nelson⁴, Christopher P Evans¹², Primo Lara¹², Robert E Reiter¹³, Owen Witte¹⁴, Matthew Rettig^{13

15}, Christopher K Wong¹⁶, Alana S Weinstein¹⁶, Vlado Uzunangelov¹⁶, Josh M Stuart¹⁶, George V Thomas², Felix Y Feng^{5

17}, Eric J Small^{5

6}, Joel A Yates¹, Zheng Xia¹⁸, Joshi J Alumkal¹⁹

Affiliations

¹ Division of Hematology and Oncology, Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
² Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
³ Department of Pathology, Michigan Center for Translational Pathology, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
⁴ Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
⁵ Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
⁶ Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
⁷ Masonic Cancer Center, University of Minnesota; Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
⁸ Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, Canada.
⁹ Department of Experimental Therapeutics, BC Cancer, University of British Columbia, Vancouver, BC, Canada.
¹⁰ Duke University, Durham, NC, USA.
¹¹ Department of Urology, University of Washington, Seattle, WA, USA.
¹² University of California Davis, Davis, CA, USA.
¹³ University of California Los Angeles, Los Angeles, CA, USA.
¹⁴ Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
¹⁵ VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
¹⁶ UC Santa Cruz Genomics Institute and Department of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USA.
¹⁷ Departments of Radiation Oncology and Urology, University of California San Francisco, San Francisco, CA, USA.
¹⁸ Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA. xiaz@ohsu.edu.
¹⁹ Division of Hematology and Oncology, Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. jalumkal@med.umich.edu.

^# Contributed equally.

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.

Publication types

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

MeSH terms

Androgen Receptor Antagonists / pharmacology
Benzamides
Biopsy
Cell Line, Tumor
Drug Resistance, Neoplasm / genetics
E2F1 Transcription Factor* / metabolism
Humans
Male
Nitriles
Phenylthiohydantoin
Prostatic Neoplasms, Castration-Resistant* / drug therapy
Prostatic Neoplasms, Castration-Resistant* / genetics
Prostatic Neoplasms, Castration-Resistant* / metabolism
RNA
Receptors, Androgen / genetics
Receptors, Androgen / metabolism

Substances

Androgen Receptor Antagonists
Benzamides
E2F1 Transcription Factor
Nitriles
Receptors, Androgen
Phenylthiohydantoin
RNA
enzalutamide

Abstract

Publication types

MeSH terms

Substances

Grants and funding