At first, it was believed that the MLK family cannot activate MEK-ERK signaling, the mitogenic pathway for cell proliferation, which is only regulated by another subgroup of MAP3Ks, RAF proto-oncogene kinases (RAFs) [8]; however, it was later demonstrated that all the members of the MLK family (MLK1-MLK4) can activate the MEK-ERK pathway and lead to anti-cancer drug resistance in cancer patients undergoing treatments with RAF inhibitors [9]. This evidence concerns the gene MAP3K21 and cancer.