Predicting the path of resistance

A new mechanism, unlike any previously identified, may help explain why some recurrent ovarian tumors become resistant to treatment with commonly used platinum-based chemotherapy drugs such as cisplatin and carboplatin.
 
While these findings stem from 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. Together such genetic mistakes are thought to cause about 10 percent of ovarian cancers, said Dr. Toshi Taniguchi, senior author of the study published online Feb. 10 in the journal Nature.
 
“Because BRCA1 and BRCA2 have similar functions in terms of DNA repair, we may be able to generalize these findings for women with either mutation,” said Taniguchi, of the Human Biology and Public Health Sciences divisions.
 
BRCA2 works to repair damaged DNA; inherited mutations in this gene disrupt that ability, which increases the risk of ovarian and breast cancer. At the same time, such mutations also make cancer cells more vulnerable to DNA-damaging agents such as cisplatin and carboplatin. While ovarian tumors initially respond very well to platinum-based chemotherapy, eventually between 70 percent and 80 percent of advanced-stage ovarian-cancer patients develop a resistance to these drugs.

“The majority of advanced-stage ovarian-cancer patients die due to acquired resistance to platinum-based drugs. It is a serious problem,” Taniguchi said.

Taniguchi, first author Dr. Wataru Sakai and colleagues at the Hutchinson Center, University of Washington, Cedars-Sinai Medical Center and the Mayo Clinic uncovered how such resistance occurs. They 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,” said co-author Dr. Elizabeth Swisher, associate professor of medicine in the Department of Obstetrics and Gynecology and director of the UW’s Breast and Ovarian Cancer Prevention Program. “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,” she said.

If women with recurrent ovarian cancer 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 said.

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.

Center authors include research technician Emily Villegas and Dr. Celine Jacquemont, both of the Taniguchi Lab; Cynthia Friedman, a professional support specialist in the Trask Lab; and Dr. Nicole Urban, of the Public Health Sciences Division. 

The National Institutes of Health/National Cancer Institute, Searle Scholars Program, V Foundation, Hartwell Innovation Fund, L&S Milken Foundation, American Cancer Society California Division-Early Detection Professorship, Yvonne Betson Trust and the Hutchinson Center funded this research.