BRAF Inhibitors Linked to squamous-Cell Carcinoma in Patients with RAS Mutations

March 2012, Vol 3, No 2

As many as 15% to 30% of patients who receive BRAF inhibitors (eg, vemurafenib, dabrafenib) for the treatment of metastatic melanoma develop nonmelanoma skin cancers. Data from a new study suggest that this paradoxical effect may be caused by squamous-cell carcinoma cell lines with RAS mutation that proliferate on exposure to these drugs (Su F, et al. N Engl J Med. 2012;366:207-215). A molecular analysis identified oncogenic mutations, including HRAS, KRAS, NRAS, CDKN2A, and TP53, in lesions of patients in 3 phase 1-3 studies. All patients had metastatic melanoma with BRAF V600 mutation, and all received vemurafenib therapy; the analysis included 11 initial patients plus a validation set of 14 samples from 12 patients. All samples were analyzed for RAS mutations.

Among the 23 patients, 78% had a history of chronically sun-damaged skin, and 17% had a history of cutaneous squamous-cell carcinomas or keratoacanthomas. Of all samples, 60% had RAS mutations. Among these, 12 of the 13 initial specimens and 4 of the 8 validation samples had HRAS mutations, with HRAS Q61L being most prevalent. The effects of BRAF inhibitors on these HRAS mutations were analyzed by comparing the murine cell line B9, which harbors the HRAS Q61L mutation. In each of the 3 studies, exposure to vemurafenib led to an increased proliferation of HRAS Q61L mutant cell lines caused by a paradoxical increase in oncogenic MAPK-pathway signaling in those cells. Vemurafenib, which was recently approved by the US Food and Drug Ad min istration for malignant melanoma, appears to exacerbate preexisting nonmelanoma skin cancer. The authors of the study outlined the mechanism by which vemurafenib paradoxically potentiates skin cancers. It appears that the drug enhances MAPK activity leading to RAS gene mutations, a driver oncogene in approximately one third of cancers. This effect, however, can be blocked with the use of MEK inhibitors. This discovery may lead to the development of BRAF inhibitors that do not stimulate MAPK and RAS mutations.

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