Abstract PR05: Targeting of CDK7 inhibits super-enhancer-associated oncogenic programs in MYCN-amplified tumor cells

Abstract

Abstract The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a novel covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, would be useful therapy for cancers that are driven by MYC or its family members. Citation Format: Edmond Chipumuro, Eugenio Marco, Camilla L. Christensen, Nicholas Kwiatkowski, Tinghu Zhang, Clark M. Hatheway, Brian J. Abraham, Bandana Sharma, Caleb Yeung, Abigail Altabef, Antonio Perez-Atayde, Kwok-Kin Wong, Guo-Cheng Yuan, Nathanael S. Gray, Richard A. Young, Rani E. George. Targeting of CDK7 inhibits super-enhancer-associated oncogenic programs in MYCN-amplified tumor cells. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr PR05.