CDK12-inactivation-induced MYC signaling causes dependency on the splicing kinase SRPK1

Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an aggressive sub-group of castration-resistant prostate Cancer (CRPC). Hyper-activation of MYC transcription factor is sufficient to confer the CRPC phenotype. Here, we show that loss of CDK12 promotes MYC activity, which renders the cells dependent on the otherwise non-essential splicing regulatory kinase SRSF protein kinase 1 (SRPK1). High MYC expression is associated with increased levels of SRPK1 in patient samples, and overexpression 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 nascent transcription. This is the first study to show that Endovion is an SRPK1 inhibitor. Inhibition of SRPK1 with either of the compounds promotes transcription elongation, and transcriptionally activates the unfolded protein response. In brief, here we discover that CDK12 inactivation promotes MYC signaling in an SRPK1-dependent manner, and show that the clinical grade compound Endovion selectively targets the cells with CDK12 inactivation.

SLAM‐seq; cyclin‐dependent kinase 12; prostate cancer; splicing; synthetic lethality.