Simplified BRAF signaling network.

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Simplified BRAF signaling network. Simplified BRAF signaling network. Growth factor receptors and RTKs on tumor cells signal through RAS to BRAF to activate the MEK–ERK signaling pathway resulting in oncogenic transcriptional events and loss of cell-cycle control. Intrinsic resistance to BRAF inhibitors occurs by splice variants or amplification of BRAF-V600x mutations (x = E, K). Extrinsic resistance to BRAF drugs can occur by engagement of other receptor tyrosine kinases (EGFR and RTK) to re-engage MEK and PI3K signaling downstream of the BRAF blockade (bypass mechanism). Brion W. Murray, and Nichol Miller Mol Cancer Ther 2015;14:1975-1984 ©2015 by American Association for Cancer Research