Abstract A157: Targeting MYC dependence in cancer by inhibiting BET bromodomains.

Abstract

Abstract The MYC transcription factor is a master regulator of diverse cellular functions and has long been considered a compelling therapeutic target because of its role in a wide range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging due to both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein-DNA interactions. Here we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in a variety of genetic contexts. Inhibition of BET bromodomain-promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of cell lines. Genetic reconstitution experiments indicate that MYC predominantly mediates the phenotypes observed with BET inhibition. MYC suppression was also accompanied by deregulation of the MYC transcriptome. Treatment with a BET inhibitor resulted in significant anti-tumor activity in lymphoma and leukemia xenograft models. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A157.