Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer

Daniel J. Coleman, Lina Gao, Jacob Schwartzman, James Korkola, David Sampson, Daniel S. Derrick, Joshua Urrutia, Ariel Balter, Julja Burchard, Carly J. King, Kami E. Chiotti, Laura Heiser, Joshi Alumkal

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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.

Original languageEnglish (US)
Article number3823
JournalScientific Reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Castration
Prostatic Neoplasms
Maintenance
Androgen Receptors
Cell Line
Neoplasms
RNA Interference
Chromatin
Cell Survival
Clinical Trials
Genes
Proteins

ASJC Scopus subject areas

  • General

Cite this

Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer. / Coleman, Daniel J.; Gao, Lina; Schwartzman, Jacob; Korkola, James; Sampson, David; Derrick, Daniel S.; Urrutia, Joshua; Balter, Ariel; Burchard, Julja; King, Carly J.; Chiotti, Kami E.; Heiser, Laura; Alumkal, Joshi.

In: Scientific Reports, Vol. 9, No. 1, 3823, 01.12.2019.

Research output: Contribution to journalArticle

Coleman, DJ, Gao, L, Schwartzman, J, Korkola, J, Sampson, D, Derrick, DS, Urrutia, J, Balter, A, Burchard, J, King, CJ, Chiotti, KE, Heiser, L & Alumkal, J 2019, 'Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer', Scientific Reports, vol. 9, no. 1, 3823. https://doi.org/10.1038/s41598-019-40518-5
Coleman, Daniel J. ; Gao, Lina ; Schwartzman, Jacob ; Korkola, James ; Sampson, David ; Derrick, Daniel S. ; Urrutia, Joshua ; Balter, Ariel ; Burchard, Julja ; King, Carly J. ; Chiotti, Kami E. ; Heiser, Laura ; Alumkal, Joshi. / Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer. In: Scientific Reports. 2019 ; Vol. 9, No. 1.
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