A new class of drugs called PARP inhibitors shows great promise in treating BRCA-deficient breast and ovarian cancers. Research now indicates that targeting the BRCA pathway by inhibiting the CDK1 (cyclin-dependent kinase 1) enzyme may help PARP inhibitors attack other cancer types.
“This is the first time we are combining PARP inhibitors with another agent that's really designed for doing that,” says Geoffrey Shapiro, senior author of a paper published in June (Nat Med 2011;17:875–82).
PARP inhibitors are poster children for therapeutic treatment via “synthetic lethality,” which aims to exploit conditions in which a cell can live without either 1 of 2 genes but not without both.
PARP is required in a pathway for single-stranded DNA damage repair. When PARP is inhibited, single-strand breaks can degenerate to more serious double-strand breaks. These are corrected by a second, double-stranded DNA-repair mechanism called “homologous recombination,” which requires intact BRCA proteins. In tumors where BRCA is mutated and this second mechanism is lost, inhibiting the PARP pathway results in single-strand breaks that degenerate to unrepaired double-strand breaks that are lethal to the cell.
CDK1 aids in regulating the cell-division cycle and is frequently overactive in human cancer. In 2009, Dana-Farber Cancer Institute researchers showed that CDK1 is needed for cell-cycle checkpoint control after DNA damage, at least in part by influencing the BRCA1 pathway. Several compounds inhibiting CDK family members, including CDK1, are being partnered with chemotherapies in clinical trials for cancer.
The Dana-Farber team now has demonstrated that BRCA1-mediated DNA repair is dependent on CDK1 and that homologous recombination breaks down when CDK1 is inhibited. Inhibition of CDK1 causes a BRCA1-proficient cell to lose essential BRCA1 function.
The scientists also showed that in cancer cells with normal BRCA proteins, depleting CDK1 boosted sensitivity to PARP inhibition more than 100-fold. Tumor growth was substantially delayed in mice bearing xenografts of cancer cells when those cells were induced to deplete CDK1 and were treated with a PARP inhibitor. These results were replicated with a small molecule CDK1 inhibitor. Additionally, in a genetically engineered mouse model of aggressive lung adenocarcinoma expressing normal BRCA proteins, the combination of a CDK1 inhibitor and a PARP inhibitor almost doubled survival rates compared to mice treated with either drug alone.
Importantly, with both CDK1 and PARP inhibited, normal cells did not show significant signs of toxicity and mice demonstrated no signs of organ damage.
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