Public release date: 6-Mar-2012 [ | E-mail | Share ]

Contact: Kim Irwin kirwin@mednet.ucla.edu 310-206-2805 University of California - Los Angeles Health Sciences

Cancer is tough to kill and has many ways of evading the drugs used by oncologists to try and eliminate it.

Now, researchers at UCLA's Jonsson Comprehensive Cancer Center have uncovered how an advanced form of melanoma gets around an inhibitor, 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 a BRAF inhibitor. Quite simply, by increasing the copies of the mutated BRAF gene, the melanoma is trying to over produce the drug target protein and outnumber the inhibitor. The 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. 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," said study senior author Dr. Roger Lo, an assistant professor of dermatology and molecular and medical pharmacology and a Jonsson Cancer Center scientist. "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 radio 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."

The one-year study is published March 6, 2012, in the peer-reviewed journal Nature Communications.

About 50 percent of patients with metastatic melanoma, or 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 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 and stop patients from becoming resistant.

Lo and his team examined samples of 20 patients for this study, taking their normal tissue, their tumor tissue before treatment with Zelboraf and a sample when the cancer had responded earlier but subsequently became resistant. Using high-throughput DNA sequencing technology, the scientists examined the entire cancer exome to see what changes were occurring that may point to resistant mechanisms. Lo found that five of the 20 patients showed increased copies of the mutated BRAF gene. Cell lines developed from melanoma patients also showed pathways downstream of the amplified gene that could be blocked with inhibitors to fight resistance.

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UCLA scientists uncover mechanism for melanoma drug resistance