Therapeutic Targeting of CDK12/CDK13 in Triple Negative Breast Cancer

A subset of breast cancers harboring mutations that disrupt homologous recombination (HR) and elicit the so-called 'BRCAness' phenotype are sensitive to inhibition of poly-ADP ribose polymerase (PARP) activity, and platinum agents. Drug discovery strategies that exploit this DNA damage repair vulnerability may broaden the utility of current treatments. Disruption of HR is observed in tumor cells with mutations in cyclin-dependent kinase 12 (CDK12), and furthermore, silencing CDK12 in combination with PARP inhibition results in synthetic lethality. CDK12 along with other family members CDK7, CDK8, CDK9, and CDK13 phosphorylate the C-terminal domain (CTD) of RNA polymerase II, and play pivotal roles controlling transcription and posttranscriptional RNA processes. Specifically, CDK12 regulates the expression of a small number of key DDR pathway genes by controlling splicing and cleavage at internal polyadenylation sites. We have generated novel, potent and selective, orally bioavailable small molecule inhibitors of CDK12 and CDK13. In triple negative breast cancer (TNBC) cells, our lead molecule SR-4835, downregulates DNA damage repair proteins including ATM, ATR, BRCA1 and Rad51 leading to induction of apoptotic cell death, and acts in synergy with the chemotherapeutic agents cisplatin, irinotecan and olaparib. In preclinical efficacy studies, SR-4835 blocks tumor progression in patient derived xenograft (PDX) models of TNBC, and moreover, when dosed in combination with selected chemotherapeutic agents demonstrates tumor regression and enhanced efficacy over single agent treatment.