The BRAF V600E mutation
The BRAF V600E mutation is a missense mutation that encodes a constitutively active kinase, resulting in overactive signaling of the MAPK pathway (Staal et al., 2018). This hyperactivation of the MAPK pathway is associated with a wide range of cancers, such as melanoma (Eggermont and Chiarion-Sileni, 2017). In order to inhibit the hyperactive MAPK pathway, targeted inhibitors of BRAF V600E/K, such as dabrafenib and vemurafenib, have been developed (Dudek et al., 2019). These drugs act by targeting and inhibiting BRAF V600E/K, however, their effectiveness is diminished due to paradoxical ERK1/2 activation in tissues with wild-type BRAF (Chien et al., 2021). Paradoxical ERK1/2 activation is linked to secondary cancers, meaning that targeted inhibitors of BRAF V600E/K alone are not sufficient for complete inhibition of the MAPK pathway. To further inhibit MAPK pathway hyperactivation, MEK inhibitors are often combined with BRAF V600E/K inhibitors, thus blocking the upstream activating signal to BRAF V600E/K (Amado et al., 2016). Cont…
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