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This Week in NEJM: Jan 19, 2012

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In NEJM this week, an international team of researchers reports a study of RAS mutations in patients with cutaneous squamous cell carcinoma who were treated with BRAF inhibitors. The team analyzed oncogenic mutations in the lesions of 21 patients treated with BRAF inhibitor vemurafenib. Out of the 21, 13 had RAS mutations, the team found, as did eight out of 14 samples in a validation set. The most prevalent was HRAS Q61L, the team writes, adding that "increased proliferation of HRAS Q61L–mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)–pathway signaling and activation of ERK-mediated transcription." In a mouse model of HRAS Q61L–mediated skin carcinogenesis, the researchers found that a concomitant treatment with a MEK inhibitor blocked the growth of lesions harboring HRAs mutations.

In a related editorial in NEJM this week, the Wistar Institute's Ashani Weeraratna says that while BRAF inhibitors have helped many melanoma patients, the "paradox" of these drugs is the development of cutaneous squamous-cell carcinomas and keratoacanthomas that occur in response to treatment. Recent data reveals the mutations behind these secondary cancers have certain implications for how oncologists use BRAF inhibitors, Weeraratna says. For one, all patients being given these drugs should also be tested for RAS mutations. "Second," she adds, "these data underscore how critical it is to understand the mechanism of action of targeted therapies, which not only will alert us to potential clinical toxic effects (e.g., squamous-cell carcinomas), but can help us rationally design alternative or complementary therapies (e.g., MEK inhibition)."

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