These data confirmed that p-ERK1/2 rebound and autophagy induction, the previously reported adaptive resistance mechanisms to MEK1/2 and/or SHP2 inhibition, are driving MIA PaCa-2 and HCT 116 cancer cell growth and suggest that the combination of IACS-13909 with trametinib can obliterate both SHP2-dependent and -independent drug resistance mechanisms. The gene discussed is MAPK3; the disease is cancer.