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UCLA scientists uncover mechanism for melanoma drug resistance
Date:3/6/2012

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

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