The inhibition of mutant BRAF has been shown to induce ERK activation in RAS-mutant cells, which can lead to tumorigenesis. A patient with BRAF-V600E-mutant melanoma undergoing treatment with the BRAF inhibitor vemurafenib developed NRAS-mutant leukaemia, and Abdel-Wahab and colleagues tested whether combined BRAF and MEK inhibition would control both malignancies. They found that intermittent treatment (to keep toxicities under control) with vemurafenib plus concurrent intermittent treatment with the MEK inhibitor cobimetinib caused remission of the melanoma and suppressed progression, proliferation and ERK activation of the leukaemia. These responses have, so far, lasted for 20 months.
References
Abdel-Wahab, O. et al. Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF and NRAS mutant malignancies. Cancer Discov. http://dx.doi.org/10.1158/2159-8290.CD-13-1038 (2014)
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Alderton, G. Combination and dosing schedule are key. Nat Rev Cancer 14, 215 (2014). https://doi.org/10.1038/nrc3717
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DOI: https://doi.org/10.1038/nrc3717