Researchers at Vanderbilt University Medical Center (VUMC) have discovered a protein that may lead to a new way to prevent resistance and improve outcomes for patients whose cancers have mutations in the tumor suppressor gene BRCA2.
The protein, RADX, is a DNA-binding protein. It regulates the activity of an enzyme called RAD51, which helps repair tumor-promoting DNA breaks and ensure an accurate copy of the DNA is made during cell division. RAD51, in turn, is gathered up and transported to the sites of DNA damage and DNA replication by the BRCA2 protein.
Mutations in the BRCA2 gene disrupt the DNA repair and replication functions of the BRCA2/RAD51 pathway, increasing the risk of cancers of the breast, ovaries, prostate and pancreas as well as melanoma.
Since BRCA2 mutations also reduce the ability of tumor cells to repair broken DNA, these cells are sensitive to DNA-damaging anti-cancer drugs like cisplatin and newly approved DNA repair inhibitors like Olaparib. If the cells acquire secondary mutations that restore normal BRCA2function, however, they can become resistant to the drugs.
This is the case with ovarian cancer. Within six months one quarter of ovarian tumors will become resistant to cisplatin. Only a third of patients survive beyond five years, making ovarian cancer the fifth-leading cause of cancer death among women in the United States.
RADX, the protein discovered by the Vanderbilt scientists, may be a key to understanding and overcoming this resistance.
In a paper published this week by the journal Molecular Cell, David Cortez, Ph.D., and colleagues describe how RADX regulates the activity of RAD51 in a way that promotes genome stability and modulates drug sensitivity.
Much remains to be learned. But if, as suspected, RADX determines how tumors respond to therapy, it could be a target for efforts to overcome resistance, the researchers concluded.
The paper’s first authors were Huzefa Dungrawala, Ph.D., a postdoctoral fellow in the Cortez lab, and graduate student Kamakoti Bhat. Cortez is Ingram Professor of Cancer Research and professor of Biochemistry in the Vanderbilt University School of Medicine, and co-leader of the Genome Maintenance Program in the Vanderbilt-Ingram Cancer Center.
The research was supported in part by National Institutes of Health grants GM116616, CA092584, CA212435 and GM118089.