Nutlin-3a inducesKRASmutant lung cancer specific methuosis-like cell death that is dependent on GFPT2

Abstract

AbstractOncogenicKRASmutation, the most frequent mutation in non-small cell lung cancer (NSCLC), is an aggressiveness risk factor and leads to the metabolic reprogramming of cancer cells by promoting glucose, glutamine, and fatty acid absorption and glycolysis. Lately, sotorasib was approved by the FDA as a first-in-classKRAS-G12C inhibitor. However, sotorasib still has a derivative barrier, which is not effective for otherKRASmutation types, except for G12C. Additionally, resistance to sotorasib is likely to develop, demanding the need for alternative therapeutic strategies. 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. This further elucidated non-apoptotic and catastrophic macropinocytosis associated methuosis-like cell death, which was found to be dependent on GFPT2 of the hexosamine biosynthetic pathway, specifically inKRASmutant NSCLC cells. These results indicate the potential of nutlin-3a as an alternative agent for treatingKRASmutant NSCLC cells.