Transcriptional profiling identifies an androgen receptor activity-low, stemness program associated with enzalutamide resistance

Joshi J. Alumkal, Duanchen Sun, Eric Lu, Tomasz M. Beer, George V. Thomas, Emile Latour, Rahul Aggarwal, Jeremy Cetnar, Charles J. Ryan, Shaadi Tabatabaei, Shawna Bailey, Claire B. Turina, David A. Quigley, Xiangnan Guan, Adam Foye, Jack F. Youngren, Joshua Urrutia, Jiaoti Huangi, Alana S. Weinstein, Verena FriedlMatthew Rettig, Robert E. Reiter, Daniel E. Spratt, Martin Gleav, Christopher P. Evans, Joshua M. Stuart, Yiyi Chen, Felix Y. Feng, Eric J. Small, Owen N. Witte, Zheng Xia

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The androgen receptor (AR) antagonist enzalutamide is one of the principal treatments for men with castration-resistant prostate cancer (CRPC). However, not all patients respond, and resistance mechanisms are largely unknown. We hypothesized that genomic and transcriptional features from metastatic CRPC biopsies prior to treatment would be predictive of de novo treatment resistance. To this end, we conducted a phase II trial of enzalutamide treatment (160 mg/d) in 36 men with metastatic CRPC. Thirty-four patients were evaluable for the primary end point of a prostate-specific antigen (PSA)50 response (PSA decline ≥50% at 12 wk vs. baseline). Nine patients were classified as nonresponders (PSA decline <50%), and 25 patients were classified as responders (PSA decline ≥50%). Failure to achieve a PSA50 was associated with shorter progression-free survival, time on treatment, and overall survival, demonstrating PSA50's utility. Targeted DNA-sequencing was performed on 26 of 36 biopsies, and RNA-sequencing was performed on 25 of 36 biopsies that contained sufficient material. Using computational methods, we measured AR transcriptional function and performed gene set enrichment analysis (GSEA) to identify pathways whose activity state correlated with de novo resistance. TP53 gene alterations were more common in nonresponders, although this did not reach statistical significance (P = 0.055). AR gene alterations and AR expression were similar between groups. Importantly, however, transcriptional measurements demonstrated that specific gene sets-including those linked to low AR transcriptional activity and a stemness program-were activated in nonresponders. Our results suggest that patients whose tumors harbor this program should be considered for clinical trials testing rational agents to overcome de novo enzalutamide resistance.

Original languageEnglish (US)
Pages (from-to)12315-12323
Number of pages9
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number22
DOIs
StatePublished - Jun 2 2020

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. Support includes Stand Up to Cancer-Prostate Cancer Foundation (PCF) Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409. This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Other support includes The Pacific North-west Prostate Cancer Specialized Programs of Research Excellence (SPORE)/ National Cancer Institute (NCI) Grant P50 CA097186; the Michigan Prostate SPORE/NCI Grant P50 CA186786; the Knight Cancer Institute Biostatistics Shared Resource at Oregon Health & Science University Grant P30 CA069533-16 and P30 CA051008-16; a Rogel Scholar Award through the University of Michigan Rogel Cancer Center; and the Wayne D. Kuni and Joan E. Kuni Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, the University of Michigan Rogel Cancer Center, or the Wayne D. Kuni and Joan E. Kuni Foundation. Oregon Health & Science University received research funding from Astellas/Pfizer to conduct this investigator-initiated trial. We thank Eva Rodansky and Joel Yates for help with manuscript preparation.

Funding Information:
Author contributions: J.J.A., T.M.B., E.J.S., and O.N.W. designed research; J.J.A., D.S., E. Lu, T.M.B., G.V.T., E. Latour, R.A., J.C., C.J.R., S.T., S.B., C.B.T., D.A.Q., X.G., A.F., J.F.Y., J.U., J.H., A.S.W., V.F., M.R., R.E.R., D.E.S., M.G., C.P.E., J.M.S., Y.C., F.Y.F., E.J.S., O.N.W., and Z.X. performed research; J.J.A., D.S., E. Lu, G.V.T., E. Latour, X.G., J.H., A.S.W., V.F., J.M.S., Y.C., O.N.W., and Z.X. analyzed data; and J.J.A., D.S., E. Lu, and Z.X. wrote the paper. Reviewers: M.C., Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins; M.L., Weill-Cornell Medical College; and R.P., Indiana University Simon Comprehensive Cancer Center. Competing interest statement: J.J.A. has received consulting income from Janssen Biotech and Merck, and honoraria for speaker’s fees from Astellas. T.M.B. has received research funding from Alliance Foundation Trials, Boehringer Ingelheim, Corcept Therapeutics, Endocyte Inc., Janssen Research & Development, Medivation, Inc./Astellas, OncoGenex, Sotio, and Theraclone Sciences/OncoResponse; consulting fees from AbbVie, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Clovis Oncology, GlaxoSmithKline, Janssen Biotech, Janssen Japan, Merck, Novartis, and Pfizer; and stock ownership in Salarius Pharmaceuticals, and Arvinas Inc. J.H. serves as a consultant for Morehealth, OptraScan, Genetron, Gencode, York Biotechnology, Kingmed Diagnostics, and Gem Flower Healthcare and is a founder of Sisu Pharma. M.R. received research funding from Novartis, Johnson & Johnson, Merck, Astellas, and Medivation; is a member of a speakers’ bureau for Johnson & Johnson and Bayer; and served as a consultant for Constellation Pharmaceuticals. F.Y.F. has received consulting income from Astellas, Bayer, Celgene, Janssen, Sanofi, Genentech, and EMD Serono and has ownership interest (including patents) in PFS Genomics and Nutcracker Therapeutics. E.J.S. has received honoraria for speaker’s fees from Janssen; consulting income from Janssen, Fortis Therapeutics, Beigene, and Tolero; and stock ownership in Fortis Therapeutics and Harpoon Therapeutics. O.N.W. currently has consulting, equity, and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, Break-through Properties, and Allogene Therapeutics. None of these companies contributed to or directed any of the research reported in this article. T.M.B. and M.C. are coauthors on a 2019 article. D.E.S. and M.L. are coauthors on a 2019 article. None of the other authors have any relevant disclosures to declare. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND). 1To whom correspondence may be addressed. Email: jalumkal@med.umich.edu or owenwitte@mednet.ucla.edu. 2Present address: Division of Hematology and Oncology, Department of Internal Medicine, Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109. 3Present address: Division of Hematology and Oncology, Department of Internal Medicine, University of California, Los Angeles Jonsson Comprehensive Cancer Center, Los Angeles, CA 90095.

Funding Information:
Support includes Stand Up to Cancer-Prostate Cancer Foundation (PCF) Prostate Dream Team Translational Cancer Research Grant SU2C-AACR-DT0409. This research grant is made possible by the generous support of the Movember Foundation. Stand Up To Cancer is a program of the Entertainment Industry Foundation administered by the American Association for Cancer Research. Other support includes The Pacific Northwest Prostate Cancer Specialized Programs of Research Excellence (SPORE)/ National Cancer Institute (NCI) Grant P50 CA097186; the Michigan Prostate SPORE/NCI Grant P50 CA186786; the Knight Cancer Institute Biostatistics Shared Resource at Oregon Health & Science University Grant P30 CA069533-16 and P30 CA051008-16; a Rogel Scholar Award through the University of Michigan Rogel Cancer Center; and the Wayne D. Kuni and Joan E. Kuni Foundation. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, the University of Michigan Rogel Cancer Center, or the Wayne D. Kuni and Joan E. Kuni Foundation. Oregon Health & Science University received research funding from Astellas/Pfizer to conduct this investigator-initiated trial. We thank Eva Rodansky and Joel Yates for help with manuscript preparation.

Publisher Copyright:
© 2020 National Academy of Sciences. All rights reserved.

Keywords

  • Androgen receptor
  • Enzalutamide
  • Resistance
  • Stemness

PubMed: MeSH publication types

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

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