Blocking DNA Repair Increases Drug Sensitivity of Lung Cancer Cells

Cancer researchers are testing drugs that prevent tumor cells from repairing the damage to their DNA that was caused by treatment with certain chemotherapeutic agents.

Investigators from the Dana-Farber Cancer Institute (Boston, MA, USA) first damaged the DNA of nonsmall-cell lung cancer cells growing in culture by treating them with the drug cisplatin. The damaged DNA initiated a series of events, called a "checkpoint cascade,” and two major checkpoint proteins, cdk1 and cdk2, activated pathways to suspend the cell cycle until the damaged DNA could be repaired.

In the current study, the investigators blocked cdk1 activity in order to determine its suitability as a drug target. Results published in the August 14, 2009, issue of the journal Molecular Cell revealed that when cdk1 was inactivated the cells failed to suspend the cell cycle for DNA repair. The investigators then showed that the lack of cdk1 disrupted the performance of the major DNA repair protein, BRCA1.

"What we have shown suggests that you can use these drugs to sensitize cancer cells to DNA-damaging chemotherapy,” explained senior author Dr. Geoffrey Shapiro, associate professor of medicine at the Dana-Farber Cancer Institute. "This is a mechanism by which these inhibitory drugs may be synergistic with DNA-damaging agents. These results explain the observations seen in clinical trials currently being conducted at Dana-Farber and elsewhere. The data give us confidence to go ahead with testing of cdk inhibitors in combination with DNA-damaging chemotherapy.”

Related Links:
Dana-Farber Cancer Institute