Combined treatment with two drugs targeting different points in the same growth-factor pathway delayed the development of treatment resistance in patients with BRAF-positive metastatic malignant melanoma. The results of a phase I/II study of treatment with the kinase inhibitors dabrafenib and trametinib were published online on September 29, 2012 in the New England Journal of Medicine (NEJM) and are being released online to coincide with a presentation at the European Society for Medical Oncology meeting in Vienna. "We investigated this combination because of research we and others have conducted into the molecular underpinnings of resistance to BRAF inhibitor therapy," says Keith Flaherty, M.D., of the Massachustts General Hospital (MGH) Cancer Center, lead author of the NEJM report and principal investigator of the study. "We found that adding the MEK inhibitor trametinib to BRAF inhibitor dabrafenib clearly delays the emergence of resistance. In fact, the combination was at least twice as effective as BRAF inhibition alone." In approximately half of patients with metastatic melanoma, tumor growth is driven by mutations that keep the BRAF protein – part of the MAPK cell growth pathway – constantly activated. In recent years, drugs that inhibit BRAF activity have rapidly halted and reversed tumor growth in about 90 percent of treated patients, but most patients' response is temporary, with tumor growth resuming in six or seven months. Investigations into how this resistance emerges have suggested that the MAPK pathway gets turned back on through activation of MEK, another protein further down the pathway. Based on promising results of animal studies, the current investigation was designed to test whether inhibiting both the BRAF and MEK proteins could delay treatment resistance.
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