Research unlocks how melanoma resists new drug combination therapy

Researchers at the UCLA Jonsson Comprehensive Cancer Center have uncovered how melanoma becomes resistant to a new drug combination therapy consisting of BRAF+MEK inhibitor - chemical compounds used to fight cancer.

During the two-year study led by Dr. Roger Lo, the research team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitors and then after the patients relapsed after the melanoma developed resistance to the drug therapy. The participants had all benefited from the combo therapy initially, but after a timeframe of a few months to more than a year, the tumors that had initially regressed, started to grow again.

After obtaining biopsies of the tumours, the researchers extracted and analysed the genetic material. This analysis provided leads for the investigators to study how melanoma cells grown in Lo's laboratory rewired their growth circuitry to get around the combo inhibitors.

Lo's team found that the melanoma cells resist the combo therapy of BRAF+MEK inhibitors by developing highly unusual changes in certain key cancer genes. These signature changes or configurations not only mark the presence of drug resistance melanoma cells but also indicate to researchers 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 combo 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 Dr. Antoni Ribas, JCCC member and professor of hematology and oncology, and a co-author of the study. ''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 with advanced stage or metastatic melanoma, about 8,000 people will die of the disease each year. About 50 per cent of people with metastatic melanoma, have tumours that harbour a mutated protein called a mutated BRAF protein. The presence of this mutated BRAF protein is what makes a patient with metastatic melanoma appropriate for the BRAF+MEK combo inhibitor therapy.

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 Zelboraf (vemurafenib) and was approved by the FDA in 2011.

These studies have provided critical insights that led to development of the current combo 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.

The study is published online in the journal Cancer Cell.

The research was funded by the National Institutes of Health (NIH), the Melanoma Research Alliance, and Stand Up To Cancer.