Previously, we found that KRAS mutant cancer cells showed variable response to AZD6244, a MEK inhibitor through differential activation of EGFR/AKT. To investigate its mechanism, we performed cDNA microarray using four KRAS mutant cancer cells. We found that treatment with AZD6244 reduced the expression of mitogen-inducible gene 6 (MIG6), a negative feedback regulator for EGFR, in AZD6244-resistant cells, while activity of EGFR and AKT was increased in these cells. Reconstitution or knockdown of MIG6 expression affected cancer cell responses to AZD6244. Treatment with a combination of EGFR inhibitor and AZD6244 inhibited cell proliferation synergistically without activation of AKT in AZD6244-resistant cells. Our study provides a mechanism of differential response to MEK inhibition in KRAS mutant cancer.