Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1

Aberrant activation of the RAS family of guanosine triphosphatases (GTPases) is prevalent in lung adenocarcinoma, with somatic mutation of KRAS occurring in similar to 30% of tumors. We previously identified somatic mutations and amplifications of the gene encoding RAS family GTPase RIT1 in lung adenocarcinomas. To explore the biological pathways regulated by RIT1 and how they relate to the oncogenic KRAS network, we performed quantitative proteomic, phosphoproteomic, and transcriptomic profiling of isogenic lung epithelial cells in which we ectopically expressed wild-type or cancer-associated variants of RIT1 and KRAS. We found that both mutant KRAS and mutant RIT1 promoted canonical RAS signaling and that overexpression of wild-type RIT1 partially phenocopied oncogenic RIT1 and KRAS, including induction of epithelial-to-mesenchymal transition. Our findings suggest that RIT1 protein abundance is a factor in its pathogenic function. Therefore, chromosomal amplification of wild-type RIT1 in lung and other cancers may be tumorigenic.

Automated summary

Mutant KRAS and RIT1 were found to promote canonical RAS signaling, while overexpression of wild-type RIT1 partially phenocopied oncogenic RIT1 and KRAS, inducing epithelial-to-mesenchymal transition. The study suggests that RIT1 protein abundance plays a role in its pathogenic function, and chromosomal amplification of wild-type RIT1 in lung and other cancers may be tumorigenic.