Abstract IA21: Targeting amplified MYCN through CDK7 inhibition in high-risk neuroblastoma

Abstract

Listen

Translate article

Abstract Neuroblastoma, a tumor of the peripheral nervous system, is the most common extracranial malignancy of childhood. It often presents with widely disseminated disease, leading to survival rates that seldom exceed 50% regardless of treatment strategy. Amplification of the MYCN oncogene, which occurs in over half of high-risk cases is the most unequivocal marker of aggressive disease, automatically stratifying patients to more intensive therapy. However this target has proved elusive for a number of reasons, which include the lack of a druggable domain and the absence of an unequivocal MYCN target-gene signature. The identification of the oncogenic role of MYC as a universal amplifier of transcription in MYC-overexpressing cancer cells provides a new paradigm for understanding how this oncogene promotes the cancer state and suggests a novel focus - RNA polymerase II (Pol II) - for the development of targeted therapy. The transcription cycle of RNA polymerase II is governed by a group of cyclin-dependent kinases, with critical roles in transcriptional initiation, pause release and elongation. We chose to investigate CDK7, because of its dual roles in transcriptional regulation and cell cycle progression, the latter, through its CDK-activating kinase function. By using a novel, highly selective, covalent inhibitor of CDK7 that binds to a unique cysteine residue outside its ATP-binding site, we demonstrated striking activity specifically against MYCN-overexpressing neuroblastoma cells that was accompanied by a global decrease in Pol II-mediated transcription. Selective inhibition of CDK7 not only depleted short-lived transcripts involved in cell cycle progression and apoptosis regulation, but importantly, also downregulated MYCN, itself a short-lived target. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without introducing discernible toxicity. We demonstrated that as with deregulated MYC, amplified MYCN is a global transcriptional regulator that can induce massive activation of genes involved in multiple cellular processes, and that CDK7 disruption led to inhibition of MYCN-dependent transcriptional amplification. Another general feature of deregulated MYCN that seemed highly relevant to its effective targeting was its own transcriptional regulation by super-enhancers (SEs). The selective effect of THZ1 was associated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known lineage-specifying genes in neuroblastoma. This study provides a compelling rationale for targeting CDK7 to block MYCN-mediated global transcription in high-risk neuroblastoma. The challenge now is to exploit the exquisite sensitivity of SEs to transcriptional perturbation, to ensure more durable control over the progression of MYCN-driven tumor cells. Citation Format: Rani George. Targeting amplified MYCN through CDK7 inhibition in high-risk neuroblastoma. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr IA21.