CDK12 and CDK13 in oncology: from RNA regulation to therapeutic targeting

This review aims to synthesize current knowledge on Cyclin-dependent kinase 12 (CDK12) and Cyclin-dependent kinase 13 (CDK13), two transcriptional kinases with distinct and overlapping roles in gene regulation, genome stability, and cancer biology. These kinases control transcription elongation and co-transcriptional processing, including splicing and polyadenylation, thereby linking RNA polymerase II activity with DNA repair and replication stress response. CDK12 and CDK13 play context-specific roles across malignancies, where amplification, truncating mutations, fusions, and deletions variably alter their transcriptional output and downstream DNA repair programs. Their dysregulation contributes to oncogenesis, metastasis, and resistance to conventional therapies. There is growing therapeutic interest in CDK12/13 inhibition, especially as selective inhibitors of single DNA repair nodes have shown limited success. Selective CDK12/13-targeting agents have shown efficacy in preclinical models by inducing synthetic lethality, restoring sensitivity to PARP inhibitors, and are being explored to potentiate immune checkpoint blockade. This review highlights the biological rationale for targeting CDK12 and CDK13 in cancer, summarizes emerging therapeutic strategies, and identifies key opportunities for integrating these approaches into precision oncology.