@article{c27a7906fd1a486cb597c76f7144b240,
title = "Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer",
abstract = "The BET bromodomain protein BRD4 is a chromatin reader that regulates transcription, including in cancer. In prostate cancer, specifically, the anti-tumor activity of BET bromodomain inhibition has been principally linked to suppression of androgen receptor (AR) function. MYC is a well-described BRD4 target gene in multiple cancer types, and prior work demonstrates that MYC plays an important role in promoting prostate cancer cell survival. Importantly, several BET bromodomain clinical trials are ongoing, including in prostate cancer. However, there is limited information about pharmacodynamic markers of response or mediators of de novo resistance. Using a panel of prostate cancer cell lines, we demonstrated that MYC suppression—rather than AR suppression—is a key determinant of BET bromodomain inhibitor sensitivity. Importantly, we determined that BRD4 was dispensable for MYC expression in the most resistant cell lines and that MYC RNAi + BET bromodomain inhibition led to additive anti-tumor activity in the most resistant cell lines. Our findings demonstrate that MYC suppression is an important pharmacodynamic marker of BET bromodomain inhibitor response and suggest that targeting MYC may be a promising therapeutic strategy to overcome de novo BET bromodomain inhibitor resistance in prostate cancer.",
author = "Coleman, {Daniel J.} and Lina Gao and Jacob Schwartzman and Korkola, {James E.} and David Sampson and Derrick, {Daniel S.} and Joshua Urrutia and Ariel Balter and Julja Burchard and King, {Carly J.} and Chiotti, {Kami E.} and Heiser, {Laura M.} and Alumkal, {Joshi J.}",
note = "Funding Information: Competing Interests: Dr. Alumkal has performed consulting or held an advisory role with Astellas Pharma, Bayer, and Janssen Biotech, Inc. OHSU has received institutional research funding from Aragon Pharmaceuticals Inc., Astellas Pharma, Norvartis, Zenith Epigenetics Ltd, and Gilead Sciences Inc. These interests had no role in the design or conduct of this study. Funding Information: The authors wish to thank other members of the Alumkal and Heiser labs for critical feedback and review. We also thank Sunil Joshi for technical assistance with western blotting, and the OHSU Massively Parallel Sequencing Shared Resource for performing short-read sequencing assays. We also thank the following funding sources: (1) National Institutes of Health (NIH)/National Cancer Institute (NCI) R01 award CA178610, (2) Pacific Northwest Prostate Cancer SPORE/NCI (P50 CA097186), (3) Cancer Center Support Grant (CCSG) (P30 CA069533), (4) Oregon Clinical and Translational Research Institute (OCTRI) (UL1TR000128) from the National Center for Advancing Translational Sciences (NCATS), a component of the NIH; (5) Department of Defense Synergistic Idea Award (W81XWH-13-1-0420), (6) Department of Defense Impact Awards (W81XWH-16-1-0597, W81XWH-16-1-1601), (7) Hope Foundation Award, (8) Stand Up to Cancer - Prostate Cancer Foundation - 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 (7465sc)); (9) Prospect Creek Foundation, and (10) Wayne D. Kuni and Joan E. Kuni Foundation. Publisher Copyright: {\textcopyright} 2019, The Author(s).",
year = "2019",
month = dec,
day = "1",
doi = "10.1038/s41598-019-40518-5",
language = "English (US)",
volume = "9",
journal = "Scientific Reports",
issn = "2045-2322",
publisher = "Nature Publishing Group",
number = "1",
}