Inhibition of cyclin‐dependent kinases 12/13 using CT7439 as a treatment for colorectal cancer with CDK12 upregulation

Cyclin‐dependent kinase (CDK) 12 and its paralog, CDK13, phosphorylate RNA polymerase II, enabling transcriptional elongation. In solid tumors, CDK12 loss promotes progression by inducing replication‐transcription conflict and fueling genomic instability. However, we have uncovered upregulation of CDK12 and CDK13 in ~5% of colorectal cancer (CRC) specimens, suggesting a role in cancer cell survival. Based on this, we postulated that CDK12/13 inhibition in CRC may represent a useful therapeutic strategy. To test this, we screened CDK12 and CDK12/13 inhibitors across multiple cancer cell lines and patient‐derived organoids (PDO) from a range of solid tumors, demonstrating potent activity in CRC PDO. Using siRNA‐mediated knockdown, we identified CDK13 as a potential mechanism of resistance to CDK12‐specific inhibition. Mechanistically, CDK12/13 inhibition led to a decreased abundance of BRCA1 long transcripts, rendering cells susceptible to combination therapy with PARP inhibitors. To further assess the clinical utility of CDK12/13 inhibition, we focused on CRC, for which there is an urgent need for additional therapies. We tested the efficacy of CT7439, a novel CDK12/13 inhibitor and cyclin K degrader, which showed cytotoxicity in the low nanomolar range, reduced BRCA1 expression, and concomitant DNA damage. Together, our data support further clinical development of CDK12/13 inhibition in CRC.