Oncogenic RIT1 mutations confer ferroptosis vulnerability in lung adenocarcinoma.

Abstract

Members from the RAS GTPase superfamily have been closely implicated in the tumorigenesis of various human cancers. Recent sequencing analysis of lung adenocarcinoma has revealed the prevalence of alterations in the RIT1 gene that is a close RAS paralog. However, relative to RAS subfamily members KRAS, NRAS, and HRAS, our characterization of RIT1 oncogenic properties remains incomplete. Therefore, further investigation on RIT1 will facilitate future development of targeted therapies. Our bioinformatic analysis revealed that RIT1 alterations in lung cancer predicted poor survivals but differed from its RAS paralogs by showing largely amplification and mutation. Through biochemical characterization of RIT1 hotspot mutations, we propose that RIT1 alterations were associated with increased protein abundance that promoted cell growth. Transcriptomic profiling indicated that oncogenic RIT1 mutant expression influenced common tumorigenic RAS/MAPK, PI3K/AKT, and E2F1 pathways, in addition to altered NFE2L2 target expression. Importantly, RIT1 mutants markedly sensitized cells to ferroptosis induction, and RIT1 knockdown suppressed ferroptotic cell death. Lung adenocarcinoma NCI-H2110 cells containing endogenous RIT1 M90I mutation were susceptible to ferroptosis induction both in vitro and in vivo within xenograft models. Hence, our study unravels a novel aspect of RIT1 mutations in lung cancer and suggests ferroptosis induction as a potential therapeutic strategy to treat lung cancer patients carrying RIT1 mutations.