@article{5c7edc4aa42f4b53bf98933efaa43eb5,
title = "Copy number loss of 17q22 is associated with enzalutamide resistance and poor prognosis in metastatic castration-resistant prostate cancer",
abstract = "Purpose: The purpose of this study was to measure genomic changes that emerge with enzalutamide treatment using analyses of whole-genome sequencing and RNA sequencing. Experimental Design: One hundred and one tumors from men with metastatic castration-resistant prostate cancer (mCRPC) who had not been treated with enzalutamide (n ¼ 64) or who had enzalutamide-resistant mCRPC (n ¼ 37) underwent whole genome sequencing. Ninety-nine of these tumors also underwent RNA sequencing. We analyzed the genomes and transcriptomes of these mCRPC tumors. Results: Copy number loss was more common than gain in enzalutamide-resistant tumors. Specially, we identified 124 protein-coding genes that were more commonly lost in enzalutamide-resistant samples. These 124 genes included eight putative tumor suppressors located at nine distinct genomic regions. We demonstrated that focal deletion of the 17q22 locus that includes RNF43 and SRSF1 was not present in any patient with enzalutamide-na{\"i}ve mCRPC but was present in 16% (6/37) of patients with enzalutamide-resistant mCRPC. 17q22 loss was associated with lower RNF43 and SRSF1 expression and poor overall survival from time of biopsy [median overall survival of 19.3 months in 17q22 intact vs. 8.9 months in 17q22 loss, HR, 3.44 95% confidence interval (CI), 1.338-8.867, log-rank P ¼ 0.006]. Finally, 17q22 loss was linked with activation of several targetable factors, including CDK1/2, Akt, and PLK1, demonstrating the potential therapeutic relevance of 17q22 loss in mCRPC. Conclusions: Copy number loss is common in enzalutamide-resistant tumors. Focal deletion of chromosome 17q22 defines a previously unappreciated molecular subset of enzalutamide-resistant mCRPC associated with poor clinical outcome.",
author = "Xiangnan Guan and Duanchen Sun and Eric Lu and Urrutia, {Joshua A.} and Reiter, {Robert Evan} and Matthew Rettig and Evans, {Christopher P.} and Primo Lara and Martin Gleave and Beer, {Tomasz M.} and Thomas, {George V.} and Jiaoti Huang and Aggarwal, {Rahul R.} and Quigley, {David A.} and Adam Foye and Chen, {William S.} and Jack Youngren and Weinstein, {Alana S.} and Stuart, {Joshua M.} and Feng, {Felix Y.} and Small, {Eric J.} and Zheng Xia and Alumkal, {Joshi J.}",
note = "Funding Information: Theraclone Sciences/OncoResponse (research funding), Zenith Epigenetics (research funding), personal fees and other from Arvinas (consulting fees, stock holder), grants and personal fees from Astellas Pharma (research funding, consulting fees) and Boehringer Ingelheim (research funding, consulting fees), personal fees from Astra-Zeneca (consulting fees), Bristol-Myers Squib (consulting fees), Bayer (consulting fees), Clovis Oncology (consulting fees), GlaxoSmithKline (consulting fees), Janssen Biotech (consulting fees), Merck (consulting fees), Novartis (consulting fees), Pfizer (consulting fees), and Tolero (consulting fees), and other from Salarius Pharmaceuticals (stock holder) outside the submitted work. J. Huang reports grants from Prostate Cancer Foundation during the conduct of the study. R.R Aggarwal reports grants from Prostate Cancer Foundation during the conduct of the study, grants from Janssen and AstraZeneca, Novartis, Amgen, Zenith Epigenetics, and Xynomic Pharmaceuticals, grants and personal fees from Merck, and personal fees from Dendreon outside the submitted work. F.Y. Feng reports personal fees from Astellas (consultant), Bayer (consultant), Janssen (consultant), Myovant (consultant), Roivant (consultant), Sanofi (consultant), and Genentech (consultant), and other from PFS Genomics (co-founder) outside the submitted work. E.J. Small reports grants from Stand up to Cancer/Prostate Cancer Foundation during the conduct of the study, personal fees from Janssen (advisory board), Fortis Therapeutics (advisory board), Harpoon Therapeutics (advisory board), and Tolero Therapeutics (advisory board), personal fees from Teon Therapeutics (consulting), and personal fees from Beigene Therapeutics outside the submitted work. J.J Alumkal reports grants from Stand Up to Cancer Foundation, Prostate Cancer Foundation, Kuni Foundation, and NCI during the conduct of the study, grants and personal fees from Astellas (consulting and research support to institution) and Janssen Biotech (consulting and research support to institution), personal fees from Merck (consulting) and Dendreon (consulting), grants from Zenith Epigenetics (research support to institution), Gilead Sciences (research support to institution), and Aragon Pharmaceuticals (research support to institution) outside the submitted work. No potential conflicts of interest were disclosed by the other authors. Funding Information: M.B. Rettig reports personal fees from Janssen, Bayer, Amgen, Ambryx, Clovis, and Pfizer; grants from Novartis and Progenics, as well as nonfinancial support from Merck and Astellas outside the submitted work; and is listed as a co-inventor on a provisional patent application on small molecule inhibitors of the androgen receptor that is owned by UCLA and the Department of Veterans Affairs and is not yet licensed. T.M. Beer reports grants from Alliance Foundation Trials (research funding), Corcept Therapeutics (research funding), Endocyte Inc. (research funding), Harpoon Therapeutics (research funding), Janssen Research & Development (research funding), Medivation, Inc. (research funding), Sotio (research funding), Funding Information: This research was supported by Stand Up To Cancer-Prostate Cancer Foundation - Prostate Cancer Dream Team Translational Cancer Research Grant (SU2C-AACR-DT0812 to J.A. Urrutia, R.E. Reiter, M. Rettig, C.P. Evans, P. Lara, M. Gleave, T.M. Beer, G.V. Thomas, J. Huang, R.R. Aggarwal, D.A. Quigley, A. Foye, W.S. Chen, J. Youngren, A.S. Weinstein, J.M. Stuart, F.Y. Feng, E.J. Small, and J.J. Alumkal). Stand Up To Cancer (SU2C) is a division of the Entertainment Industry Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C; Pacific Northwest Prostate Cancer SPORE/NCI (P50 CA097186 to J.J. Alumkal); Department of Defense (DOD) Synergistic Idea Award (W81XWH-13-1-0420 to J.J.Alumkal); NIH (K01LM012877 to Z. Xia). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or DOD. Other support includes: Wayne D. Kuni and Joan E. Kuni Foundation (to J.J. Alumkal) and a University of Michigan Rogel Scholar Award (to J.J. Alumkal).",
year = "2020",
month = sep,
doi = "10.1158/1078-0432.CCR-19-2303",
language = "English (US)",
volume = "26",
pages = "4616--4624",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "17",
}