Epigenetic regulations have been increasingly recognized as an integral part of tumor biology and attractive therapeutic targets. The bromodomain and extra-terminal domain (BET) proteins specifically recognize acetylated lysine residues on histone tails. BET bromodomain inhibition with a first-in-class inhibitor JQ1 reduces expression of a broad spectrum of growth promoting and antiapoptotic genes, including c-Myc, resulting in suppression of several hematopoietic cancers and NUT midline carcinoma. We and other groups have previously reported the critical role of c-Myc in glioblastoma stem cells. Here, we demonstrated broad antineoplastic effects of JQ1 both in ex vivo cultures and orthotopic models using a panel of glioblastoma tumors carrying different genetic lesions. JQ1 induced marked cell cycle arrest and apoptosis in association with p21WIP1/CIP1 induction and hTERT, Bcl-2 and Bcl-xL reduction. Consistent with previous studies, JQ1 decreased c-Myc expression in glioblastoma. However, exogenous c-Myc did not significantly protect glioblastoma from JQ1, unlike the observations in hematopoietic cancers. Cells genetically engineered for Akt hyperactivation or p53/Rb inactivation did not compromise JQ1 efficacy, suggesting that these signaling pathways commonly altered in glioblastoma may not confer resistance to JQ1. Taken together, our results suggest potentially broad therapeutic utility of BET bromodomain inhibition for treating genetically diverse glioblastoma tumors.

Citation Format: Jialiang Wang, Zhixiang Cheng. Inhibition of BET bromodomain targets genetically diverse glioblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1018. doi:10.1158/1538-7445.AM2013-1018