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UCLA researchers discover drug resistance mechanisms in most common form of melanoma
Date:11/24/2010

ving drug resistance," said Lo, an assistant professor of dermatology. "In a big portion of cases where cancers acquire resistance to targeted drugs, the oncogene being targeted finds a way to get around the drug by developing other additional mutations."

Cancers, Lo said, are very adept at finding ways around the drugs being used to fight them.

"You hit it with an axe, but the cancer soon finds a way to mitigate the effects of the axe," he said.

Lo and his team found that these mutually exclusive mechanisms of acquired drug resistance account for about 40 percent of the patients who were treated with PLX4032 and later acquired resistance to it. In some cases, Lo found that the cancer cells began overexpressing a cell surface protein that created an alternate survival pathway for the cancer while the BRAF survival pathway was being blocked by PLX4032. In other cases, a second oncogene, NRAS, became mutated, allowing the cancer to short circuit the PLX4032-inhibited BRAF mutation and reactivate the BRAF survival pathway. PLX4032 does not target the NRAS mutation, so the cancer can begin to regrow.

Lo said he expects to find other mechanisms of resistance in the remaining 60 percent of relapsing patients where neither of the two new mechanisms were found.

"It's important to find all the mechanisms of acquired drug resistance in this type of melanoma and figure out how to target them using drugs designed to hit those specific mechanisms," he said. "We've found two mechanisms in two subsets of melanoma and we'll need different drugs to treat those two subsets."

Going forward, Lo and his team will study the resistance mechanisms of the two subsets discovered and any others uncovered later to perhaps find better targets for therapy. For example, targeting the cell surface protein overexpression may prove more difficult than finding what causes the overexpression further upstream and homing in on that.

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

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