MAP2K4 and cancer: This in turn leads to activation of a number of HER family receptor tyrosine kinases whose downstream signaling limits the efficacy of MEK inhibitor monotherapy (Fig. 7a).26 It was shown recently that tumors that lack a wild type KRAS allele have increased MEK inhibitor sensitivity.39 We show here that cancer cells that have inactivating mutations in MAP3K1 or MAP2K4 are sensitive to MEK inhibitor monotherapy by disabling the positive feedback loop that limits drug responsiveness (Fig. 7b).