Journal
SCIENTIFIC REPORTS
Volume 9, Issue -, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41598-019-40518-5
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Funding
- National Institutes of Health (NIH)/National Cancer Institute (NCI) R01 award [CA178610]
- Pacific Northwest Prostate Cancer SPORE/NCI [P50 CA097186]
- Cancer Center Support Grant (CCSG) [P30 CA069533]
- Oregon Clinical and Translational Research Institute (OCTRI) from the National Center for Advancing Translational Sciences (NCATS), NIH [UL1TR000128]
- Department of Defense Synergistic Idea Award [W81XWH-13-1-0420]
- Department of Defense Impact Awards [W81XWH-16-1-0597, W81XWH-16-1-1601]
- Hope Foundation Award
- Stand Up to Cancer - Prostate Cancer Foundation Prostate Dream Team Translational Cancer Research Grant [SU2C-AACR-DT0409]
- Movember Foundation [7465sc]
- Prospect Creek Foundation
- Wayne D. Kuni and Joan E. Kuni Foundation
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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.
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