CDK10 loss primes tumor cells for transcriptional vulnerability and sensitizes to CDK12/13 inhibition.

CDK12 and CDK13, two transcriptional cyclin-dependent kinases (CDKs), are emerging as therapeutic targets in epithelial cancers due to their vital roles in transcriptional elongation and maintaining genomic stability. However, the absence of predictive biomarkers may impede the clinical use of CDK12/13 inhibitors. Here, we identify CDK10 as a consistent and kinase-dependent regulator of sensitivity to CDK12/13 inhibition. A genome-wide CRISPR-Cas9 screen across six breast and ovarian cancer models reveals CDK10 loss as a top-ranked enhancer of response to the selective CDK12/13 inhibitor CTX-439. Functional validation in multiple cancer cell lines and xenograft models shows that CDK10 deficiency boosts apoptotic responses and increases the antitumor effects of CDK12/13 inhibition. Mechanistically, CDK10 loss extends the duration of CTX-439-induced transcriptional suppression and delays RNA polymerase II re-engagement at sensitive gene loci, exemplified by CAPN7 and SENP6. These findings indicate CDK10 as a probable biomarker for patient stratification and as a co-target to boost the efficacy of transcriptional therapies. Our work reveals a previously underappreciated role for CDK10 in transcriptional resilience, emphasizing its potential to guide and enhance CDK12/13-based cancer treatments.