Inhibition of cyclin‐dependent kinases 12/13 using <scp>CT7439</scp> as a treatment for colorectal cancer with <scp>CDK12</scp> 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.