A CDK9 Inhibitor May Suppress Tumor Growth and Enhance Immunotherapy

In cancer, epigenetic reprogramming can result in silencing of tumor suppressor genes, but there are few epigenetic drugs available to reverse these modifications. To identify epigenetic drugs and targets, Zhang and colleagues performed a live cell screen of a natural compound library. This screen identified several aminothiazole compounds that reactivated an epigenetically silenced reporter gene. Connectivity mapping to identify drugs with similar transcriptional profiles suggested that these compounds inhibit CDK9, a cyclin-dependent kinase that promotes transcriptional elongation. Screening 77 additional aminothiazole analogues uncovered MC180295 as the most potent CDK9 inhibitor. CDK9 inhibition with MC180295 treatment promoted global reactivation of epigenetically silenced genes, an unexpected effect based on its role in promoting transcriptional activation as the catalytic subunit of the P-TEFb complex. Mechanistically, CDK9 directly phosphorylated the SWI/SNF complex component BRG1, an ATP-dependent helicase that regulates chromatin structure, and BRG1 was required for gene reactivation by CDK9 inhibition. CDK9 inhibition resulted in reduced BRG1 phosphorylation, and assay for transposase-accessible chromatin sequencing (ATAC-seq) demonstrated that MC180295 treatment resulted in a global and diffuse relaxation of chromatin, indicating that CDK9 is essential in the maintenance of heterochromatin compaction. In vivo, CDK9 inhibition reduced tumor growth and extended survival in tumor-bearing mice without apparent toxicity. Further, CDK9 inhibition activated endogenous retroviruses and triggered an interferon response, effects that might enhance the efficacy of immunotherapy. Indeed, in ovarian cancer xenografts, CDK9 inhibition boosted sensitivity to anti–PD-1 therapy. In addition to uncovering a role for CDK9 in maintaining heterochromatin and epigenetic gene silencing, these findings suggest that CDK9 inhibition may have antitumor activity alone or in combination with immunotherapy.

Zhang H, Pandey S, Travers M, Sun H, Morton G, Madzo J, et al. Targeting CDK9 reactivates epigenetically silenced genes in cancer. Cell 2018 Oct 25 [Epub ahead of print].

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