Effect of inhibition of SRPK1 and CDK12 on transcription and splicing in castration resistance prostate cancer cells

Inactivation of CDK12 characterizes an aggressive sub-group of castration-resistant prostate cancer (CPRC), and CRPC is currently a lethal disease. Hyper-activation of MYC transcription factor is sufficient to confer the CRPC-phenotype. Here, we show that the loss of CDK12 promotes MYC activity, which renders the cells addicted on the splicing regulatory kinase SRPK1. High MYC expression is associated with increased levels of SRPK1 in patient samples, and over-expression of MYC sensitizes prostate cancer cells to SRPK1 inhibition using pharmacological and genetic strategies. We show that Endovion (SCO-101), a compound currently in clinical trials against pancreatic cancer, phenocopies the effects of the well-characterized SRPK1 inhibitor (SRPIN340) on the nascent transcription, splicing and the overall transcriptional program. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, causes defects in splicing and transcriptionally activates the unfolded protein response. In brief, here we show that CDK12 inactivation promotes MYC-signaling in an SRPK1-dependent manner and identify the clinical grade compound Endovion, which selectively targets the cells with CDK12 inactivation. SLAM-seq after 4 hours treatment of 22RV1 cells with 150nM THZ531, 20micromolar SRPIN340 or 50micromolar Endovion.