Melanoma patients whose cancers are caused by BRAF gene mutation become resistant to Plexxikon’s expertimental drug through another genetic mutation or the overexpression of a cell surface protein, according to researchers with UCLA's Jonsson Comprehensive Cancer Center. They say that both factors drive survival of the cancer and account for relapse.
The BRAF mutation is reportedly found in 50% to 60% of melanoma patients. UCLA’s research, published November 24 in the early online edition of Nature, was conducted on Plexxikon’s PLX4032, which is in Phase III melanoma trials. The drug is also being tested in Phase II against colorectal cancer and metastatic cancer.
In a clinical trial at UCLA's Jonsson Cancer Center and other locations, patients with BRAF-mutated metastatic melanoma showed a good response to PLX4032. However, the responses were short lived, averaging seven to nine months.
Roger Lo, M.D., senior author of the Nature paper, and his team spent two years studying tissue taken from patients enrolled in the Jonsson Cancer Center study to try to determine the mechanism of resistance. They also developed drug-resistant cell lines.
It had been theorized that BRAF was finding a way around the experimental drug by developing a secondary mutation. However, Dr. Lo’s group determined that was not the case. Instead they uncovered two mutually exclusive mechanisms of acquired drug resistance, which accounted for about 40% of the patients who acquired resistance to PLX4032.
In some cases Dr. 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 called NRAS became mutated, allowing the cancer to short-circuit the PLX4032-inhibited BRAF mutation and reactivate the BRAF survival pathway.
Dr. Lo expects to find other mechanisms of resistance in the remaining 60% of relapsing patients. “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 says. “We've found two mechanisms in two subsets of melanoma, and we'll need different drugs to treat those two subsets.”