Blocking Cdk1 Protein May Sensitize More Tumors to PARP Inhibitors - July 12, 2011 • Volume 8 / Number 14

Blocking Cdk1 Protein May Sensitize More Tumors to PARP Inhibitors
July 12, 2011 • Volume 8 / Number 14

Investigators have found a potential way to compromise DNA repair in cancer cells that lack BRCA mutations, making them sensitive to treatment with PARP inhibitors. The results of the research, which was led by Dr. Geoffrey Shapiro of Dana-Farber Cancer Institute and Harvard Medical School, were published online June 26 in Nature Medicine.

Cancer cells that have BRCA mutations respond to treatment with PARP inhibitors because they have a defect in the DNA-repair pathway that becomes critical for cells when the DNA-repair pathway that involves PARP is disabled. The researchers hypothesized that blocking the activity of a protein called Cdk1 might create an effect similar to a BRCA mutation in cancer cells that lack such a mutation. Cdk1 controls the function of the normal BRCA1 protein in DNA repair and helps regulate the cell cycle.

To test their hypothesis, the researchers blocked Cdk1 function in several cancer-cell lines lacking BRCA mutations using either RNA interference or drugs designed to inhibit Cdk1 activity.

After blocking Cdk1 function and exposing the cells to gamma radiation, which damages DNA, they observed a 70 to 80 percent reduction in the formation of the DNA-repair machinery that can compensate for inhibition of the DNA-repair pathway that involves PARP.

When the researchers used RNA interference to block Cdk1 activity in two different cell lines lacking BRCA mutations, the cells were 100 to 200 times more sensitive to treatment with a PARP inhibitor than the same cell lines with normal Cdk1 levels. They saw similar results after blocking Cdk1 function with a drug.

In lung tumors lacking BRCA mutations that were grown in genetically engineered mice, the combination of a drug to block Cdk1 activity and a PARP inhibitor caused sustained tumor regression in 9 out of 13 mice that were treated for 3 weeks. Two of the mice remained alive 15 weeks after treatment without additional tumor growth. No damage to normal tissues or organs was observed with the drug combination.

The authors proposed that the combination of drugs should be tested in early-phase clinical trials. “Our hope is that doses of the Cdk1 inhibitor and the PARP inhibitor that we would study in clinical trials would be effective without harming normal tissues,” explained Dr. Shapiro.
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