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The molecular context of vulnerability for CDK9 suppression in triple wild-type melanoma

Approximately half of melanoma tumors lack a "druggable" target and are unresponsive to current targeted therapeutics. One proposed approach for treating these therapeutically-orphaned tumors is by targeting transcriptional dependencies ("oncogene starvation"), whereby survival factors are depleted through inhibition of transcriptional regulators. A drug screen identified a cyclin-dependent kinase 9(CDK9) inhibitor (SNS-032) to have therapeutic selectivity against BRAFwt/NRASwt melanomas compared to BRAFmut/NRASmut melanomas. We then used two strategies to inhibit CDK9 in vitro- a CDK9 degrader (TS-032) and a selective CDK9 kinase inhibitor (NVP-2). At 500 nM, both TS-032 and NVP-2 demonstrated greater suppression of BRAFwt/NRASwt/NF1wt cutaneous and uveal melanomas (BNFwt) than mutant melanomas (BNFmut). RNAseq analysis of 8 melanoma lines with NVP-2 treatment demonstrated that the context of this vulnerability appears to converge on a cell cycle network which includes many transcriptional regulators such as the E2F family members. Human TCGA melanoma tumor data further supported a potential oncogenic role for E2F1/E2F2 in BRAFwt/NRASwt/NF1wt tumors and a direct link to CDK9. Our results suggest that transcriptional blockade through selective targeting of CDK9 is an effective method of suppressing therapeutically-orphaned BRAF/NRAS/NF1 wild-type melanomas.

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S1145 SNS-032 (BMS-387032) SNS-032 (BMS-387032) has firstly been described as a selective inhibitor of CDK2 with IC50 of 48 nM in cell-free assays and is 10- and 20-fold selective over CDK1/CDK4. It is also found to be sensitive to CDK7/9 with IC50 of 62 nM/4 nM, with little effect on CDK6. SNS-032 (BMS-387032) induces apoptosis.

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Apoptosis related CDK