RIT1 Drives Oncogenic Transformation and is an Actionable Target in Lung Adenocarcinoma

RIT1 is a small GTPase of the RAS family, and RIT1 mutations have been identified in lung cancer, leukemias, and the developmental disorder Noonan syndrome. Mutations in RIT1 lead to increased protein levels due to impaired proteolysis, resulting in dysregulation of RAS/MAPK signaling and other pathways. Here, we documented the diversity of RIT1 mutations in human lung cancer and showed that physiological expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Evaluation of complementary methods to either inhibit RIT1 directly or the downstream RAS/MAPK pathway revealed that RIT1 M90I tumors are sensitive to SHP2 inhibitors and RAS nucleotide exchange inhibition. Additionally, a proof-of-concept chemical biology approach identified that RAS tri-complex inhibitors bind directly to GTP-bound RIT1, resulting in tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors.