‘Translating' CDK9 inhibitor effects to target prostate cancer

Introduction Prostate cancer (PC) is the most common male cancer, and more effective treatments are needed to control the late-stage disease. In the lethal disease, termed castration-resistant PC (CRPC), cancer cells sustain a pro-proliferative gene expression program despite the presence of anti-androgens. This gene expression program is ultimately dependent on CDK9, and compounds targeting it are currently in clinical trials for solid tumors. All cells depend on CDK9 to sustain gene expression, although it is not clear why cancer cells are particularly sensitive to CDK9 targeting drugs. Experimental procedures Multi-omics profiling of prostate cancer cell lines was used to understand how cells respond to CDK9 inhibition. Patient samples were used to correlate some of the findings, with data validation ongoing in syngeneic mouse models. Summary of the data We show that CDK9 inhibition activates the innate immune response through viral mimicry in PC cells. As expected, targeting CDK9 suppresses overall transcription; however, some genes are expressed in significantly higher levels in this situation. Mechanistically, CDK9 inhibition uncouples the mRNA-processing machinery from RNA polymerase II, and we show that in this situation intron retention is significantly increased. The generated mis-spliced RNAs are prone to form double-stranded RNAs (dsRNA), and full activity of (dsRNA)-activated kinase is required for the CDK9 inhibitor-induced anti-proliferative effects. Accumulation of dsRNAs is known to activate the innate immune response and indeed we show that CDK9 inhibition leads to excessive secretion of immunogenic cytokines. Conclusions Our data reveal that targeting the transcription elongation kinase CDK9 activates immuno-modulatory signalling in vitro by selectively augmenting translation of certain mRNAs. We are now validating these effects in syngeneic animal models, patient derived organoids, and probing the extent to which the transcriptional and translational programs are rewired. In the long run, our aim is to develop an effective treatment strategy against CRPC.