2. Academic Validation
  3. Maintenance of MYC expression promotes de novo resistance to BET bromodomain inhibition in castration-resistant prostate cancer

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

  • Sci Rep. 2019 Mar 7;9(1):3823. doi: 10.1038/s41598-019-40518-5.
Daniel J Coleman 1,  Lina Gao 1,  Jacob Schwartzman 1,  James E Korkola 1 2,  David Sampson 1,  Daniel S Derrick 1 2,  Joshua Urrutia 1,  Ariel Balter 3,  Julja Burchard 3,  Carly J King 1 2,  Kami E Chiotti 1 4,  Laura M Heiser 5 6,  Joshi J Alumkal 7 8
Affiliations

Affiliations

  • 1 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201, USA.
  • 2 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97201, USA.
  • 3 Computational Biology Program, Oregon Health & Science University, Portland, OR, 97201, USA.
  • 4 Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97201, USA.
  • 5 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201, USA. [email protected].
  • 6 Department of Biomedical Engineering, Oregon Health & Science University, Portland, OR, 97201, USA. [email protected].
  • 7 Knight Cancer Institute, Oregon Health & Science University, Portland, OR, 97201, USA. [email protected].
  • 8 Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, 97201, USA. [email protected].
PMID: 30846826 DOI: 10.1038/s41598-019-40518-5
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.

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