Researchers Uncover New Mechanism of Resistance to Melanoma Drug
Researchers have discovered a new way that melanoma cells may become resistant to treatment with vemurafenib (Zelboraf), a targeted therapy that has produced dramatic, if transitory, results for some patients with advanced disease. In some cases, the drug has caused tumors to shrink and even disappear, but the treatment invariably stops working.
By exposing melanoma cells in the laboratory to the drug for extended periods, Dr. David Solit of Memorial Sloan-Kettering Cancer Center and his colleagues have learned that some resistant cells produce a shortened version of the mutant BRAF protein that vemurafenib targets. The shortened protein—which is missing its middle section—is active even in the drug's presence, the researchers reported online November 23 in Nature.
"This is a common mechanism whereby the melanoma tumors overcome the effects of the drug," said Dr. Solit, noting that 6 of 19 patients with resistant tumors had a form of the protein that had been shortened in this way. "We hope that this discovery will lead to more effective treatments."
Vemurafenib blocks growth-promoting signals activated by a mutation in the BRAF gene known as V600E. In August, the Food and Drug Administration (FDA) approved the treatment for patients with unresectable or metastatic melanoma whose tumors have this mutation, which is found in about 60 percent of melanomas.
In their study, Dr. Solit and his colleagues found that the shortened forms of the BRAF V600E protein represent splicing variants—that is, they arose through a change in the processing of the RNA that was transcribed from the gene.
"This is an important study because it identifies the first resistance mechanism to BRAF inhibitors that involves a structural change in BRAF itself," said Dr. Ravi Amaravadi of the Perelman School of Medicine at the University of Pennsylvania, who treats patients with melanoma and was not involved in the study.
It will be important to determine how widespread this resistance mechanism is compared to other proposed resistance mechanisms, Dr. Amaravadi added.
So far, the investigators have found this form of the BRAF V600E protein only in vemurafenib-resistant tumors. They believe that the splicing alteration is specific to BRAF and does not affect splicing in general, suggesting that it could have arisen from a mutation or an epigenetic change.
"Conceptually, we have found a novel form of resistance for any drug," said Dr. Solit. "As happens with other targeted therapies, the drug stops working—but the mechanism is different."
—Dr. Ravi Amaravadi
With drugs such as imatinib (Gleevec) or erlotinib (Tarceva), for example, resistance often occurs when tumors acquire new genetic mutations that prevent a drug from binding to its molecular target. As these resistance mechanisms have been discovered, the knowledge has been used to develop second-generation drugs, such as dasatinib (Sprycel), which can bind to mutant forms of the BCR-ABL kinase to which imatinib cannot bind.
With vemurafenib, the shortened BRAF protein forms complexes within cells that promote growth signals in the presence of the drug. To overcome the resistance, researchers could try to develop more potent drugs and find ways to disrupt the complexes, the authors noted.
Another strategy involves combining drugs that target different proteins, an approach that is already being tried. In June, for example, researchers reported positive preliminary results from an early-phase study testing a BRAF inhibitor in combination with a drug that inhibits a second kinase, MEK, which is part of the same signaling pathway as BRAF. Consequently, the use of a MEK inhibitor could prevent or delay development of a drug-resistant form of BRAF.
"Based on the results of our study, we hypothesize that the combination of the BRAF inhibitor and the MEK inhibitor will be more effective and less toxic than either drug alone," said Dr. Solit. "But we need a randomized study to test this idea."
Studies are also needed to fully characterize the molecular basis for the altered RNA processing that leads to resistance to vemurafenib, as well as to identify additional mechanisms that lead to vemurafenib resistance. If drugs were developed to address the altered RNA processing, these agents could be administered with vemurafenib, Dr. Solit noted.
Dr. Amaravadi agreed. The development of new drugs directed against the molecular changes caused by the BRAF splice variant could "significantly prolong the clinical benefit of BRAF inhibitors," he predicted.
"This study identifies RNA processing as a potentially common resistance mechanism," said co-author Dr. Tom Misteli of NCI's Center for Cancer Research. The findings add to research suggesting the importance of alternative splicing as a mechanism of disease, he added.
"The number of splicing diseases is growing, yet our efforts to target RNA processing as a therapeutic strategy are minimal at the moment," Dr. Misteli said. "RNA therapy offers a largely unexplored, powerful therapeutic strategy."