In this study, we found that nutlin-3a, an MDM2 antagonist, inhibited the KRAS-PI3K/Akt-mTOR pathway and disrupted the fusion of both autophagosomes and macropinosomes with lysosomes, resulting in non-apoptotic and catastrophic micropinocytosis associated methuosis-like cell death, which was dependent on GFPT2 of the hexosamine biosynthetic pathway (HBP), in KRAS MT/p53 wild type (WT) NSCLC cells specifically; the results were further verified in vivo. The gene discussed is PIK3CA; the disease is non-small cell lung carcinoma.