Simultaneously blocking both cyclin-dependent kinase 1 (Cdk1) and poly(ADP-ribose) polymerase (PARP) could represent a new strategy for treating cancers regardless of their BRCA mutation status, researchers claim. A Harvard Medical School team has identified a role for Cdk1 in BRCA1-mediated homologous recombination, and shown both in vitro and in vivo that depletion or inhibition of Cdk1 compromised the ability of cancer cells with normal BRCA1 to repair DNA, increasing their sensitivity to PARP inhibition.
Geoffrey I. Shapiro, M.D., and colleagues report that inhibiting both Cdk1 and PARP in BRCA–wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts in experimental mice, and significant tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Reporting their findings in Nature Medicine, the scientists conclude that “depletion or inhibition of Cdk1 creates a state of ‘BRCAness’ in transformed cells and represents a rational approach for expanding the efficacy of PARP inhibitors to BRCA-proficient cancer populations.” Their published paper is titled “Compromised CDK1 activity sensitizes BRCA-proficient cancers to PARP inhibition.”
BRCA1’s involvement in cell cycle checkpoints is known to rely on the cell cycle protein Cdk1, and in cells lacking Cdk1, BRCA1’s checkpoint activity is compromised, Dr. Shapiro and colleagues report. The kinase phosphorylates BRCA1, and this phosphorylation is necessary for BRCA1 to efficiently form foci at sites of DNA damage and to facilitate checkpoint activation.
BRCA1 is in addition crucial to the repair of double-stranded DNA breaks by the process of homologous recombination. In cancers that display BRCA1 mutations, this deficit in homologous recombination capacity can be exploited through treatment with PARP inhibitors. PARP is responsible for repairing less lethal single-stranded DNA breaks, but in the absence of PARP the single-stranded breaks progress to double-stranded breaks, which need the BRCA1-mediated homologous recombination machinery for repair. If BRCA1 is mutated in a cancer, the double-stranded breaks that occur when PARP is inhibited chemically can’t be repaired, causing irreversible cell damage and ultimately apoptosis.
Although only cancers with BRCA1 mutations are susceptible to PARP inhibitors, the Harvard research has now found that BRCA1’s role in homologous recombination also relies on Cdk1. This hints at the possibility that inhibiting Cdk1 protein may provide another way of making BRCA1 ineffective in terms of its ability to mediate homologous recombination, potentially providing the means to sensitize cancers with a normal BRCA1 gene to PARP inhibitors.
The team’s work in vitro showed that inhibiting Cdk1 using siRNAs or small molecules—including a PARP inhibitor currently being evaluated in human clinical trials—blocked homologous recombination and sensitized non-small cell lung cancer cells to PARP inhibition. Cdk1 depletion induced a more than 100-fold increased sensitivity to PARP inhibition, to a level that is similar to that seen in BRCA1-deficient cells. Inhibition of homologous recombination was in addition associated with a significant reduction in the formation of Rad51 foci.
Encouragingly, in mice bearing human cancers, dual treatment with a combination of different inhibitors of Cdk1 and PARP was found to significantly slow tumor growth. In some of these animals, mean tumor volume was 80% lower than the volumes of tumors in control animals treated with either one of the inhibitors.
In a different mouse model with established lung adenocarcinomas, dual Cdk1- and PARP-inhibitor treatment led to the regression of tumors in 87% of animals, by up to 82%, and without evidence of toxicity or damage to normal mouse tissues and organs. Although resistance to combination therapy treatment did develop in a number of animals by six weeks, others maintained their response and tumor regression for 15 weeks.
“Our data support the clinical development of combined Cdk1 and PARP inhibition, the authors conclude. “Analysis of Cdk-mediated phosphorylation of BRCA1 suggests that a 70–90% reduction in Cdk1 activity by small-molecule inhibitors results in sensitization to PARP inhibition in vitro, translating to substantial anti-tumor activity in vivo, and serves as a guide for the degree of inhibition that will be desirable in clinical trials.”