MD Anderson IDs gene mutations responsible for melanoma drug resistance


MD Anderson scientists have pinpointed how melanoma tumors resist the cancer drug ipilimumab: genetic mutations in an immune pathway. Testing for these mutations could be used to predict if patients will respond to the drug as well as help doctors devise combination therapies to overcome this resistance.

The genetic mutations blocked interferon-gamma (IFN-y) signaling the first “clearly defined” resistance to ipilimumab found in tumor cells, said Dr. Padmanee Sharma, professor of genitourinary medical oncology and immunology at the University of Texas MD Anderson Cancer Center, in a statement. Interferon-gamma activates immune cells and also binds to tumor surface receptors, suppressing cell growth and driving cell death, according to the statement.

Ipilimumab is a monoclonal antibody that fights cancer by blocking CTLA-4, a protein that dampens the immune response. It was approved by the FDA for metastatic melanoma. But while the drug has performed well in some patients, most patients do not respond to it: “Research has shown that ipilimumab treatment provides a significant survival benefit in about 20 percent of patients with melanoma," Sharma said in the statement. "The mechanisms responsible for the lack of clinical response in the majority of patients have remained unknown."

Sharma’s team looked at whole exome gene sequencing data for interferon-gamma pathway genes in tumors from 16 melanoma patients, according to the statement. They found 184 mutations in the 12 patients that did not respond to the drug, while they only found four mutations in responders’ tumors. They confirmed their findings in cell lines and mouse models.

The findings suggest that an 11-gene interferon-gamma pathway signature could be tested to predict patient response to ipilimumab. If successful, this could help clinicians decide whether to treat the patient with ipilimumab alone or with other drugs.