COMPROMISED CDK1 ACTIVITY SENSITIZES BRCA-PROFICIENT CANCERS TO PARP INHIBITION

Homologous recombination (HR)-defective cells, such as those lacking BRCA1/2, are hypersensitive to poly (ADP-ribose) polymerase (PARP) inhibition. However, BRCA-deficient tumors represent only a small fraction of adult cancers, potentially restricting the therapeutic utility of PARP inhibitor monotherapy. We previously showed that cyclin-dependent kinase (cdk)1 phosphorylates BRCA1, an event essential for efficient BRCA1 focus formation. Here, we show that cdk1 depletion or inhibition compromises the cellular capacity to repair DNA by HR. Combined cdk1 and PARP inhibition in BRCA wild-type cancer cells results in reduced colony formation, delayed human tumor xenograft growth and tumor regression with prolonged survival in a mouse lung adenocarcinoma model. Cdk1 inhibition did not sensitize non-transformed cells or tissues to PARP inhibition. Because reduced cdk1 activity impairs BRCA1 function and HR repair, cdk1 inhibition represents a plausible strategy for expanding the utility of PARP inhibitors to the BRCA-proficient cancer population.