Now, researchers at UCLA’s Jonsson Comprehensive Cancer Center have uncovered how an advanced form of melanoma gets around an inhibitor called Zelboraf, which targets the mutated BRAF gene.
By examining the part of the melanoma genome that encodes proteins, called the exome, Jonsson Cancer Center scientists discovered that in some patients with BRAF-mutated metastatic melanoma, the mutated BRAF gene driving the cancer becomes amplified as the cancer develops resistance to an inhibitor.
Quite simply, by increasing the copies of the mutated BRAF gene, the melanoma is trying to over-produce the protein targeted by the drug, essentially outnumbering the inhibitor. The study findings may lead to alternative ways of preventing or treating resistant melanomas.
"Understanding and solving the problem of how cancer gets around targeted drugs is arguably one of the highest priorities in modern-day cancer medicine," said the study’s senior author Roger Lo, an assistant professor of dermatology and of molecular and medical pharmacology and a Jonsson Cancer Center scientist. "In this study, we found that in some patients, the cancer simply makes more of the target, the mutated BRAF gene, so that the drug dose becomes too weak to fight the cancer.
"If you think of the mutation as a right hand and the BRAF inhibitor as a left hand and the two clasp to be effective, there’s clearly an optimal ratio to ensure the mutated gene is fully inhibited. Here, we get more of the drug target, which has the same effect as dropping the drug level."
About 50 percent of patients with metastatic melanoma, roughly 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf, two pills taken twice a day. Zelboraf was approved by the U.S. Food and Drug Administration for use in metastatic melanoma in August of 2011. Many other common human cancers, including cancers of the colon, thyroid and lung, also harbor BRAF-mutated subsets, Lo said.
Oncologists cannot give more Zelboraf to these patients to combat the increased number of mutated BRAF genes because the dose approved by the FDA is the maximum tolerated dose, Lo said. However, Zelboraf could perhaps be given with inhibitors of other cell-signaling pathways in metastatic melanoma to try to stop patients from becoming resistant.