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. This evidence concerns the gene MAP3K8 and cancer.