BET bromodomain inhibitors have emerged as a promising therapy for numerous cancer types in pre-clinical studies, but molecular indicators of tumor response are lacking. Through modeling tumor evolution by studying genetic lesions underlying the development of Neurofibromatosis Type 1 (NF1)-associated Malignant Peripheral Nerve Sheath Tumors (MPNST), a lethal sarcoma with no effective medical treatment, we identified a BRD4 dependency that serves as a controlled model system to delineate mechanisms of sensitivity or resistance to BET bromodomain inhibitors in this disease. In this study, we show that loss of NF1 and p53 is associated with increased BRD4 protein levels and partial sensitivity to BET inhibition in MPNST. Strikingly, genetic depletion of BRD4 profoundly sensitizes MPNST cells to diverse BET inhibitors in culture and in vivo, while wild-type cells are spared. Collectively, genetic and pharmacological inhibition of BRD4 reveals that BET inhibitor resistance in MPNST requires wild-type BRD4 to support growth in a bromodomain-independent manner. Our findings provide a framework for understanding BET inhibitor sensitivity and resistance within distinct molecular subsets of MPNST. In addition, discovery that a synthetic lethality exists between BET inhibition and reduced BRD4 levels nominates a BRD4-low patient subpopulation as that which might best respond to a BET inhibitor therapeutic strategy for MPNST.

Citation Format: Jonathan M. Cooper, Amish J. Patel, Zhiguo Chen, Chung-Ping Liao, Kun Chen, Yong Wang, Lu Q. Le. BET inhibitor synthetic lethality in malignant peripheral nerve sheath tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5797.