Mutant selective targeted inhibitors against BRAF V600E/K like dabrafenib and vemurafenib have been quite successful in the clinic, yet these drugs are not perfect. One issue with these drugs is paradoxical ERK1/2 activation in tissues with wild-type BRAF; a phenomena linked to secondary cancers. Please answer the following: Briefly explain how the V600E BRAF mutation results in a constitutively active kinase. The BRAF V600E mutation

BRAF V600E mutation

BRAF V600E, which encodes a missense mutation, results in an overactive signaling pathway of the MAPK (Staal, et al. (2018)). Hyperactivation of MAPK pathways is linked to a variety of cancers including melanoma (Eggermont & Chiarion-Sileni 2017). BRAF V600E/K targeted inhibitors have been designed to stop the hyperactive MAPK pathways (Dudek et.al., 2019). Although these drugs target and inhibit BRAF V600E/K but have a limited effectiveness due to paradoxical ERK1/2 activation of wild-type BRAF tissues (Chien et. al., 2021). Targeted inhibitors of BRAF V600E/K are insufficient to completely block the MAPK pathway. Paradoxical ERK1/2 activation has been linked with secondary cancers. MEK inhibitors may be used in combination with BRAFV600E/K inhibits to block the activating signal from BRAFV600E/K. (Amado, et al. 2016). Cont…