DURHAM, N.C. -- A seven-year quest to understand how breast cancer cells resist treatment with the targeted therapy lapatinib has revealed a previously unknown molecular network that regulates cell death. The discovery provides new avenues to overcome drug resistance, according to researchers at Duke Cancer Institute.
"We've revealed multiple new signaling pathways that regulate cell death," said Sally Kornbluth, PhD, vice dean of Basic Science and professor of Pharmacology and Cancer Biology at Duke University School of Medicine. "And we've shown, at least in one disease, these signaling pathways can go awry in drug resistance. It also suggests you could manipulate these other pathways to overcome drug resistance."
The researchers -- co-directed by Kornbluth and Neil Spector, M.D., associate professor of medicine at Duke -- identified a protein that effectively shuts down the signals that tell a cell to die, enabling cancer cells to keep growing. That protein, MDM2, is already generating intense interest in the cancer research community because it is a master regulator of the tumor suppressor protein called p53.
Findings are published in the May 7, 2013, issue of the journal Science Signaling.
The Duke research team, with assistance from collaborators at the University of Michigan, identified a new role for MDM2 in activating cell death pathways independent of its role in regulating p53, a known initiator of cell death. More than half of all human tumors contain a mutation or deletion of the gene that controls p53.
The researchers began by studying four different types of breast cancer cells that were able to keep growing despite treatment with lapatinib, a powerful drug that targets two growth pathways commonly disrupted in breast cancer, HER2 and epidermal growth factor receptor. They found that in each case, the drug resistance could be traced to the presence of high levels of MDM2, which was found to be
|Contact: Sarah Avery|
Duke University Medical Center