Somatic p53 mutations that are markedly overrepresented in lung cancer confer resistance to ROS-induced cell death.

Abstract

Lung cancer is among the leading causes of cancer-related death in the U.S. Cigarette smoking remains the leading risk factor for lung cancer and can cause somatic mutations in the critical tumor suppressor gene TP53, among others. Mutations in TP53 not only cause loss of wild-type function but may also introduce oncogenic, gain-of-function (GOF) properties. The frequency of missense mutations at residues p.V157 and p.R158 in p53 increases dramatically in lung cancer relative to other cancers. These p53 mutants exhibit both loss of wild-type p53 function and GOF properties, including broadly rewiring gene expression programs in lung cancer cells. Several pan-cancer hotspot mutations in p53 impart GOF activities that reprogram cellular metabolism. To refine our understanding of the GOF properties conferred by the lung-enriched p53 mutants, the cellular metabolism of cells containing mutant p53 (V157F) was investigated. Untargeted metabolomics revealed that glutathione metabolism is among the top altered metabolic pathways related to mutant p53 (V157F). p53 mutants V157F and R158L provided resistance to oxidative stress induced by both menadione and cigarette smoke extract. The cell death experienced in the absence of mutant p53 (V157F; R158L) was due to the increase in reactive oxygen species (ROS). These findings suggest that the lung-enriched mutations in p53 (V157F; R158L) confer lung cancer cells with resistance to ROS, and ROS accumulation in the absence of mutant p53 causes cell death.