Abstract
Inhibition of CDK7 with THZ1 selectively suppresses the growth of MYCN-amplified tumors.
Major finding: Inhibition of CDK7 with THZ1 selectively suppresses the growth of MYCN-amplified tumors.
Mechanism: THZ1 inhibits transcriptional amplification of super-enhancer–associated genes including MYCN.
Impact: CDK7 blockade may be a viable therapeutic strategy to target MYC function in MYC-driven cancers.
Hyperactivation of the MYC oncogene is a common transformative event in cancer and induces global amplification of protumorigenic transcriptional programs. Deactivation of MYC in experimental cancer models results in cell-cycle arrest and tumor regression; however, the development of targeted therapies against MYC has proven difficult. Chipumuro and colleagues found that THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), selectively targets MYCN-amplified neuroblastoma cells. MYCN-driven neuroblastoma cell lines displayed significantly higher sensitivity to THZ1 compared with cells lacking MYCN amplification and nontransformed cell lines and exhibited increased cell-cycle arrest and apoptosis following THZ1 treatment. Furthermore, THZ1 inhibited the growth of MYCN-amplified neuroblastoma xenograft tumors without systemic toxicity, suggesting that CDK7 blockade specifically deregulates amplified MYCN. THZ1 treatment caused a reduction in markers associated with active transcription, cell-cycle progression, and antiapoptotic signaling and led to a genome-wide decrease in the expression of actively transcribed genes in MYCN-amplified cells, which was dependent on downregulation of MYCN mRNA and protein levels. Ectopic expression of MYCN increased the sensitivity of MYCN-nonamplified cells to THZ1 and induced global transcriptional amplification, whereas MYCN depletion mimicked the effects of THZ1, supporting the idea that the cytotoxic effects of CDK7 inhibition are mediated by disruption of MYCN function. The sensitivity of MYCN-amplified neuroblastoma cells to THZ1 was driven by the presence of super-enhancers associated with the MYCN locus, other oncogenic drivers, and genes associated with sympathetic neuronal lineage–specific transcriptional regulation. Treatment of MYCN-amplified cells with THZ1 led to reduced RNA polymerase II occupancy and decreased RNA expression of super-enhancer–associated genes including MYCN. Taken together, these data identify CDK7 inhibition as a potential therapeutic strategy to target global transcriptional amplification in MYC-driven cancers.
Note: Research Watch is written by Cancer Discovery Science Writers. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://CDnews.aacrjournals.org.
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