CDK7 Inhibition Suppresses Super-Enhancer-Linked Oncogenic Transcription in MYCN-Driven Cancer

Abstract

SUMMARY 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, may be useful therapy for cancers that are driven by MYC family oncoproteins.

CRISPR-Cas9 screen reveals a MYCN-amplified neuroblastoma dependency on EZH2

“…Previous studies of MYCN-amplified neuroblastoma have focused on the role of MYCN in transcriptional activation and the superenhancer machinery to drive a neuroblastoma oncogenic program (20,43,56,57). The role of MYCN in repressing tumor suppressor programs in neuroblastoma has not been as well explored.…”

“…After 10 days of GSK126 treatment in mice, the levels of H3K27me3 were significantly MYCN stimulates tumor cell growth through activation of an oncogenic transcriptional program (20,43). Here, we hypothesized that MYCN also positively regulates the expression of EZH2 in neuroblastoma.…”

Overcoming therapeutic resistance in glioblastoma: the way forward

“…Some transcription factors were already known to maintain several types of normal stem cells (108)(109)(110), and c-Myc and OCT4 can help induce the formation of GSCs from astrocytes (111). Expression of all these transcription factors can be increased in GSCs (101)(102)(103)(104), and is controlled by extracellular signaling pathways, superenhancers (112,113), epigenetic regulation (102), and microRNAs (114,115). They also activate DNA damage repair pathways that contribute to the therapeutic resistance of GSCs (58).…”

A mouse model of MYCN-driven retinoblastoma reveals MYCN-independent tumor reemergence

“…Several studies have reported on potential MYCN-directed therapeutic approaches to reduce MYCN expression levels (14)(15)(16)(17)(18). One approach involves inhibition of aurora kinase A, which is required for MYCN protein stability (14)(15)(16).…”

“…Aurora kinase A inhibitors destabilized MYCN, suggesting a therapeutic strategy for combating MYCN-amplified tumors (15,16). Other promising approaches for targeting MYCN-amplified tumors include inhibition of BET domain proteins (17) or of CDK7 (18), both of which lead to reduced MYCN transcription. Despite excitement about the potential of targeted therapies to decrease MYCN expression in MYCNamplified tumors, whether resistance to MYCN-directed therapies will occur has not been determined in any model system.…”