Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are highly aggressive sarcomas that develop sporadically or in Neurofibromatosis type 1 (NF1) patients. MPNSTs are typically fatal, and effective treatments remain limited. To gain insights into MPNST pathogenesis, we utilized a novel MPNST mouse model that allowed us to study the evolution of these tumors at the transcriptome level. Strikingly, in MPNSTs we found upregulation of chromatin regulator Brd4, and show that BRD4 inhibition profoundly suppresses both growth and tumorigenesis. Our findings reveal new roles for BET bromodomains in MPNST development, and report a novel mechanism by which bromodomain inhibition induces apoptosis through induction of pro-apoptotic Bim, which may represent a paradigm shift in therapy for MPNST patients. Moreover, these findings indicate novel epigenetic mechanisms underlying the balance of anti-/pro-apoptotic molecules, and suggest that bromodomain inhibition can shift this balance in favor of cancer cell apoptosis.
Citation Format: Amish J. Patel, Chung-Ping Liao, Zhiguo Chen, Chiachi Liu, Yong Wang, Lu Q. Le. BET bromodomain inhibition triggers apoptosis of NF1-associated malignant peripheral nerve sheath tumors through Bim induction. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3117. doi:10.1158/1538-7445.AM2014-3117