Combination Treatment Makes Cancer Cells More Susceptible to PARP Inhibitors

Cancer researchers have shown that blocking the activity of cyclin-dependent kinase 1 (Cdk1) in cancer cells prevents the functioning of the DNA-repair enzymes breast cancer–associated 1 (BRCA1) and BRCA2, which render the cells sensitive to chemotherapy with PARP (poly(ADP-ribose) polymerase) inhibitors.

Previous studies have found that cancer cells that lack functional BRCA1 or BRCA2 were hypersensitive to inhibition of PARP. However, BRCA-deficient tumors represent only a small fraction of adult cancers, which is likely to restrict usefulness of chemotherapy based only on PARP inhibition.

Since Cdk1 phosphorylates BRCA1, which is essential for efficient formation of BRCA1 foci, investigators at the Dana-Farber Cancer Institute (Boston, MA, USA) examined the relationship between Cdk1 activity and PARP inhibition.

They reported in the June 26, 2011, online edition of the journal Nature Medicine that depletion or inhibition of Cdk1 compromised the ability of cancer cells to repair DNA by homologous recombination. Combined inhibition of Cdk1 and PARP in BRCA–wild-type cancer cells resulted in reduced colony formation, delayed growth of human tumor xenografts, and tumor regression with prolonged survival in a mouse model of lung adenocarcinoma. Inhibition of Cdk1 did not sensitize normal cells or tissues to inhibition of PARP.

Senior author Dr. Geoffrey Shapiro, professor of medical oncology at the Dana-Farber Cancer Institute, said, “The new findings suggest that by blocking CDK1, we can disable BRCA1 in many types of cancers and make them sensitive to a PARP inhibitor. It could extend the use of these drugs to a much larger group of patients.”

“We achieved tremendous responses in this mouse model,” said Dr. Shapiro. “The survival curve of the animals nearly doubled. We are quite excited about this and looking forward to evaluating this combination in clinical trials.”

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Dana-Farber Cancer Institute