Researchers find clues on how melanoma resists effective treatments

This image depicts the gross appearance of a cutaneous pigmented lesion, which had been diagnosed as superficial spreading malignant melanoma (SSMM). (CDC.gov)

Researchers believe they have discovered a mechanism by which tumors eventually evade effective combination treatments for melanoma, providing clues that could lead to longer-lasting therapies for the deadliest of skin cancers.

The two-year study, led by Dr. Roger Lo of the UCLA Jonsson Comprehensive Cancer Center, looked at tumor samples from 15 melanoma patients prior to therapy that combined a BRAF inhibitor with an MEK inhibitor and after they developed resistance to the drugs.

Previous research found that adding an MEK drug to a BRAF drug significantly lengthened the time before the disease began to worsen. That led to GlaxoSmithKline's Tafinlar and Mekinist combination, and the combination of Roche's Zelboraf with the experimental Exelixis drug cobimetinib awaiting U.S. approval.

The so-called targeted therapies are designed to turn off specific molecular pathways associated with tumor growth. The approach can have dramatic effects, until tumor cells develop resistance.

"The resistance is basically a matter of time, but if we figure out the strategies by which the resistance happens we can propose new ways to suppress these mechanisms," Lo said in a telephone interview.

"If we can understand better what type of (genetic) mutations occur in melanoma ... we can design better and better drugs to suppress these. Either new drugs, better combinations of drugs or better regimens of drugs," Lo said.

By studying genetic material from tumors that developed resistance to the combination therapy, Lo's team found highly unusual changes in key cancer genes.

"What we found was genetic alterations were much more exaggerated," Lo said.

"Most of the time when a gene is increased for the benefit of cancer, usually you see four copies, 10 copies," Lo said. "Here, we're finding 80 or 100 copies.

"This is the result of a severe evolutionary pressure imposed on the cancer by the drugs. It's almost a signature of resistance to the combo drug."

Along with the findings, published on Thursday in the journal Cancer Cell, Lo's group proposed potential ways of fighting the resistance, including intermittent therapy that would take a break from exposing the tumor to the drugs.

"Other ideas includes inhibitors that would inhibit certain types of signaling ... that specifically target mechanisms of resistance," Lo said.

"We need to study iterative resistance to therapies so we can construct better and better therapies to push the curve to increased survival."