SEATTLE—A research team led by Fred Hutchinson Cancer Research Center recently identified a new mechanism that explains why some recurrent ovarian tumors become resistant to treatment with commonly used platinum-based chemotherapy drugs such as cisplatin and carboplatin. The research appeared online Feb. 10 in the journal Nature. Ovarian cancer is currently the fifth leading cause of cancer deaths among women.
While these findings are based on the study of ovarian-cancer cells from women with inherited mutations in the BRCA2 gene, they also may help explain the mechanics of cisplatin resistance in ovarian-cancer patients with BRCA1-gene mutations, which together are estimated to cause roughly 10 percent of ovarian cancers, according to senior author Toshiyasu (Toshi) Taniguchi, M.D., Ph.D.
Taniguchi and colleagues at the Hutchinson Center, University of Washington, Cedars-Sinai Medical Center and the Mayo Clinic found that when exposed to cisplatin, some ovarian-cancer cells develop secondary mutations on their BRCA2 gene that restore the gene's ability to repair DNA. This restoration of gene function then makes the cancer cells resistant to chemotherapy.
"This event is unlike any previous mechanism of resistance to chemotherapy identified in
cancers," says co-author Dr. Elizabeth Swisher, associate professor of medicine in the
Department of Obstetrics and Gynecology and director of the Breast and Ovarian Cancer
Prevention Program at the University of Washington. "By identifying the cause of chemotherapy resistance in these cancers, we may be able to better predict who will respond to different chemotherapy agents and find novel ways to re-sensitize tumors to chemotherapy that otherwise would not have had a good response to treatment."
If women with recurrent ovarian cancer are found to have a secondary mutation on their
BRCA2 gene, their cancer likely would be resistant not only to platinum-based compounds but also other drugs such as PARP inhibitors.
"Testing whether relapsed tumors have a secondary mutation of BRCA2 may be important to predict clinical outcome," Taniguchi says.
The researchers suspect they may be able to generalize their findings regarding secondary mutations in BRCA2 to other DNA-repair genes, such as BRCA1, which may help explain drug resistance to a variety of cancers, including those of the breast, prostate and pancreas.