Abstract CN08-04: Targeting super-enhancer driven transcriptional dependencies in cancer

Abstract

Abstract Super-enhancers are acquired by cancer cells through gene amplification, translocation or transcription factor overexpression and facilitate high-level expression of genes including MYC, whose protein products are critical for the control of cell identity, growth and proliferation, and which are especially sensitive to perturbation. We demonstrate that the genomically amplified MYCN oncogene, by promoting the development of super-enhancers, leads to upregulation of the active transcriptional program of neuroblastoma cells. Using THZ1, a novel covalent inhibitor of cyclin-dependent kinase 7 (CDK7), a widely expressed regulator of transcription and cell cycle progression, we demonstrate selective targeting of MYCN-amplified neuroblastoma cells, leading to global repression of MYCN-dependent transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without toxicity to normal cells. The selectivity of THZ1 for MYCN-amplified cells was associated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known lineage-specifying genes in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by oncogenic transcription factors such as MYC. Citation Format: Rani E. George. Targeting super-enhancer driven transcriptional dependencies in cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr CN08-04.