Researchers have uncovered how melanoma becomes resistant to a promising new drug combination utilizing BRAF+MEK inhibitors after an initial period of tumor shrinkage. This study was published in Cancer Cell (2015; doi:10.1016/j.ccell.2014.11.018).

This 2-year study was led by Roger Lo, MD, PhD, of the University of California Los Angeles (UCLA) Jonsson Comprehensive Cancer Center (JCCC). During the study, Lo and his team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitor combination drugs and then after relapsed due to drug resistance. The participants had all benefited from the combination therapy initially, but after periods of time the tumors regressed.

All the tumor biopsies taken from these patients were subjected to in-depth analysis of the genetic material extracted from the tumors. This analysis of patient-derived tumors then provided leads to how melanoma cells grown in Lo’s laboratory rewired their growth circuitry to get around the inhibitors.

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Lo’s team found that the melanoma cells resist the combination of BRAF+MEK inhibitors by developing highly unusual genetic changes in certain key cancer genes. These signature genetic changes, or configurations, not only mark the presence of drug-resistant melanoma cells but also tell us about potential new ways to shut them off.

“We need to find ways to go beyond the BRAF+MEK drug combination, by possibly finding a third drug, or alter how we prescribe the [combination] of drugs,” said Lo, UCLA assistant professor of dermatology. “The idea is to eventual suppress melanoma drug resistance even before it arises.”

“In most cases, melanoma eventually becomes resistant,” said coauthor Antoni Ribas, MD, PhD, JCCC member and professor of hematology and oncology. “We now understand the molecular basis of the resistance mechanisms, which leads to the planning of new treatment approaches to disable these mechanisms.”

An estimated 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will die of the disease. Approximately 50% of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation.

Lo and Ribas previously collaborated on several seminal drug resistance studies investigating how melanoma resisted the then-experimental drug PLX4032, which is now known as vemurafenib (Zelboraf) and was approved by the FDA in 2011.

These studies have provided critical insights that led to development of the current combination therapy for melanoma using BRAF+MEK inhibitors and additional on-going clinical trials. Lo hopes this new study will also lead to more effective therapies for patients.

“If we understand how a disease fights your therapy, then we can start to design more effective treatment strategies,” Lo said.