UC Irvine

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, with von Hippel-Lindau (VHL) gene mutations prevalent in approximately 90% of cases. We have previously demonstrated synthetic lethality between VHL loss and the inhibition of Cyclin-Dependent Kinases (CDKs) in ccRCC, using the multi-CDK inhibitor Dinaciclib. Here, we extend these findings by investigating the specific role of CDK9 in synthetic lethality with VHL loss. CDK9 is a transcriptional CDK involved in the process of transcription elongation and splicing. Using three distinct and specific CDK9 inhibitors (AZD45753, KB0742 and NVP-2), we confirmed preferential toxicity towards VHL-deficient ccRCC cells that acted independently of the hypoxia-inducible factor (HIF) pathway, the main pathway regulated by VHL. An analysis of the current literature connecting inhibition of CDK9 to cancer cell death suggests that the prime mechanism of action is the reduction of CDK9’s target pro-survival proteins, MCL-1 or BFL-1. Interestingly, we found that BFL-1, not MCL-1, is the critical anti-apoptotic protein involved in the mechanism of synthetic lethality. The literature further suggested that CDK9 inhibition might cause immunogenic cell death (ICD). In vivo, immunocompetent and immunodeficient mouse studies using AZD4573 showed that CDK9 inhibition suppressed ccRCC tumor growth, although we did not observe significant changes in immune cell populations upon treatment in an immunocompetent mouse model. At the same time, CDK9 inhibition did not compromise immune system. Our results offer novel insights into the mechanism of CDK9 inhibition / VHL loss synthetic lethality in ccRCC and provide a compelling rationale for further development of CDK9 inhibitors as potential therapeutics in VHL-deficient ccRCC. The BFL-1 pathway, which is a part of the mechanism of AZD4573 action, represents a biomarker for drug sensitivity, paving the way for improved patient stratification and treatment outcomes.