Fig. 1.

Mechanisms of selective B-Raf (V600E) inhibitor resistance. a In melanoma and colon cancer, cells are known to acquire resistance to B-Raf (V600E) inhibitors through several mechanisms. The RAS-RAF-MEK-ERK or PI3K-AKT pathways can be driven by (1) upregulation or activation of receptor tyrosine kinases (RTK) such as IGF-1R, PDGFRβ, and EGFR or (2) acquired RAS-activating mutations. (3) BRAF splice variants with truncated RAS binding domains permit RAS-independent activator-receiver dimerization. (4) RAS-dependent transactivation of RAF receivers (BRAF or CRAF) by inhibitor-bound wild-type BRAF or CRAF activators. (5) Acquired MEK-activating mutations can act on ERK1/2 independently of RAS and RAF activity. (6) Increased activity of downstream kinases, such as COT, can bypass the inhibition of BRAF and directly phosphorylate MEK. b In papillary thyroid cancer, a mechanism of resistance has been demonstrated through neuregulin-1 (NRG1)-dependent activation of HER2/HER3. Activation of HER2/HER3 then drives both the RAS-RAF-MEK-ERK and/or PI3K-AKT pathways