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. 2017 Mar 6;36(27):3842–3851. doi: 10.1038/onc.2016.526

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Copyright © 2017 The Author(s)

This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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Scheme depicting mechanisms of resistance observed to BRAF and MEK1/2 inhibitors in vitro and in vivo. Resistance is largely mediated by alternative means of MAPK pathway activation. Mutations in MEK1 and MEK2 that interfere with drug binding-pockets or that upregulate inherent kinase activity mediate resistance to both BRAF and MEK inhibitors. The pathway can also be reactivated through gain-of-function NRAS^Q61H/K/R mutations, alternative splice variants of BRAF^V600E, overexpression of BRAF^V600E, CRAF or Cancer Osaka thyroid oncogene (COT1) or phosphatase and tensin homolog (PTEN) mutations. Overexpression of RTKs including platelet-derived growth factor receptor β (PDGFRβ), epidermal growth factor receptor (ERBB2), insulin-like growth factor 1 receptor (IGFR1), hepatocyte growth factor receptor (MET) and AXL RTK have also been proposed to drive resistance.