A Novel CDK12 Inhibitor Induces Homologous Recombination Deficiency to Enhance PARP Inhibitor Efficacy in Uterine...

Uterine serous carcinoma (USC) is an aggressive p53-mutated endometrial carcinoma that exhibits gene mutations in homologous recombination (HR) pathways, similar to high-grade serous ovarian carcinoma (HGSOC). However, the therapeutic effect of PARP inhibitors on USC is limited. This study investigated cyclin-dependent kinase 12 (CDK12), a transcriptional regulator of HR genes, and evaluated the efficacy of a novel CDK12 inhibitor, CTX-439, combined with a PARP inhibitor, olaparib, in patient-derived xenograft (PDX) models of USC. We evaluated the HR deficiency (HRD) scores, genetic alterations, and HR-related gene abnormalities, including CDK12, in USC, other histopathologic types of uterine endometrial carcinoma, and HGSOC using The Cancer Genome Atlas dataset. We also assessed CDK12 function and CTX-439 efficacy in USC utilizing USC cell lines and PDX models. USC exhibited a higher HRD score than other histologic subtypes of uterine endometrial carcinoma but lower than HGSOC. CDK12 amplification occurred more frequently in USC than in HGSOC but was not associated with HRD scores. Tumors with CDK12 amplification demonstrated high CDK12 expression, which correlated with poor prognosis in USC. The CDK12 inhibitor CTX-439 suppressed HR-related gene expression, including BRCA1 and BRCA2; induced apoptosis and DNA damage; and inhibited tumor growth in USC PDX models with high CDK12 expression. Furthermore, CDK12 inhibition enhanced tumor sensitivity to the PARP inhibitor olaparib in USC PDX models. This study indicates that CDK12 is a potential therapeutic target for enhancing the antitumor effects of PARP inhibitors in patients with USC.