P-099: Perturbation of CDK7 and super-enhancer driven transcriptional programs synergistically halts multiple myeloma cell proliferation

Background With the deluge of available genomic data in recent years, it is becoming evident that MM cells are characterized by cell cycle dysregulation, epigenetic heterogeneity, and perturbation of the transcriptional landscape. We here elucidated the biological role of CDK7 and explored the functional consequence of its inhibition in MM using chemical and genetic approaches, including a recently reported selective CDK7 covalent inhibitor YKL-5-124, and engineered systems for rapid CDK7 protein degradation (dTAG). As previously shown with non-selective inhibitors, CDK7 inhibition via YKL-5-124 was active against a large panel of 25 MM cell lines and observed a significant inhibition of MM cell proliferation, with a significantly lower IC50 compared to PHA-activated normal donor peripheral blood mononuclear cells (PBMCs), suggesting a specific sensitivity of MM cells to CDK7 inhibition. The efficacy of YKL-5-124 was confirmed in vivo in several murine MM models. Selective pharmacological degradation of endogenously tagged CDK7 and inducible KO/KD cell systems confirmed impact of CDK7 inhibition on MM cell proliferation supporting the view that CDK7 is a pharmacologically relevant target for MM. Gene expression analysis after CDK7 inhibition in MM1S and H929 cells revealed that transcripts for only a subset of genes were substantially affected by treatment with low dose of YKL-5-124, showing a strong leading-edge enrichment for downregulation of E2F expression program, cell cycle, DNA damage, and MYC targets. We have indeed confirmed a potent reduction in phosphorylation of RB protein, with consequent decrease of E2F activity in MM cells confirmed using E2F-driven luciferase reporter. These data support the notion of CDK7 as a central hub in the oncogenic CDK-pRb-E2F pathway in MM cells, with its expression and activity positively correlated with E2F transcriptional output in patient cells. Conclusion Importantly, dual inhibition with low doses of YKL-5-124 and BRD4 inhibitor JQ1 respectively, displayed superior activity against a panel of MM cell lines and primary MM cells compared to single perturbation alone by both converging on a subset of key SE-associated dependencies as well as impacting distinct oncogenic expression programs. Isobologram analysis revealed strong synergism with a combination index (CI)