Combination therapy with BRAF-V600E and MEK inhibitors is under investigation to overcome resistance to BRAF-V600E inhibitors. However, one-third of patients receiving this combination progress within 6 months. To identify possible mechanisms of resistance, Long et al. analysed 20 melanoma metastases with BRAF-V600E from 10 patients treated with dabrafenib (a BRAF-V600E inhibitor) and trametinib (a MEK and ERK inhibitor). They found MAPK reactivation through BRAF amplification and activating mutations of NRAS and MEK2. Interestingly, whereas MEK2-C125S mutation conferred resistance to the combination therapy, the equivalent MEK1-C121S mutant did not, highlighting a possible unique function of MEK2. As mutations in the MAPK and PI3K pathway are often already present in BRAF-V600E-mutant melanoma, the authors raise caution about combining BRAF-V600E inhibition with inhibitors of either of these pathways.
References
Long, G. V. et al. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nature Commun. 5, 5694 (2014)
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Alderton, G. Resisting combinations. Nat Rev Cancer 15, 5 (2015). https://doi.org/10.1038/nrc3889
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DOI: https://doi.org/10.1038/nrc3889