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.
"For the first time, we were able to see in actual patient tissue samples how the cancer gets around this drug by altering the target," Lo said. "It appears that the drug target is not only mutated and hyper-activated, but it's also massively over-produced in some cases of clinical relapse."
Lo said there's an experimental drug that also inhibits mutated BRAF which may be effective against this form of melanoma at a dose that does not result in substantial side effects. In that case, an oncologist might have room to increase the drug dose once a relapse driven by BRAF amplification is encountered in the clinic.
Scientists so far have discovered five mechanisms of BRAF inhibitor resistance in melanoma patients, accounting for about 60 to70 percen
|Contact: Kim Irwin|
University of California - Los Angeles Health Sciences