MAP2K1 and neoplasm: For example, mutations in the MEK kinase COT (MAP3K8) and MEK1 (encoded by MAP2K1) are closely related to inhibitory bypass resistance that develops in response to RAFi.371,407 RAFi-resistant tumor cells show the rapid recovery of MAPK pathway activation, allowing escape from RAFi therapy; therefore, the total blockade of the entire pathway is essential for stimulating apoptosis in RAF-mutant cancers.408 The combination of RAFi together with other downstream inhibitors (e.g., MEK inhibitors) can maximize MAPK pathway inhibition and minimize cancer resistance.