One is that inhibiting ERK1/2 directly prevents negative feedback regulation driven by ERK1/2 phosphorylation of upstream pathway components.43 Consistent with this, studies in melanoma have shown that inhibition of ERK1/2 can overcome BRAF and MEKi resistance from BRAF amplification or MEK1/2 mutation38 as well as increased COT activity, which have been shown to occur as resistance mechanisms to MEK1/2 inhibition.44 Finally, inhibition of ERK1/2, as the most downstream node of the MAPK pathway, has the potential to better prevent pathway reactivation.45 This evidence concerns the gene MAPK3 and melanoma.