RIT1 drives lung oncogenic transformation and is an actionable target in lung adenocarcinoma [PDX]

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 levels of this oncoprotein due to impaired proteolysis, resulting in dysregulation of RAS/MAPK and other pathways. Here we document the diversity of RIT1 mutations in human lung cancer and show that physiologic expression of RIT1 M90I is sufficient to drive autochthonous lung tumor development in vivo in mouse models. Due to the current lack of targeted therapies for this oncoprotein, we undertake different and complementary methods to either inhibit RIT1 directly or the downstream RAS/MAPK pathway. Through a proof-of-concept chemical biology approach, we discover that RAS tri-complex inhibitors bind directly to GTP-bound RIT1 and lead to tumor shrinkage. These molecules provide a feasible therapeutic approach for RIT1-driven lung tumors. Lung adenocarcinoma MSK-LX1033 was injected, and tumors were allowed to grow to approximately 300 mm³. The tumors were then treated orally for three days with RMC-7977 (10 mg/kg), RMC-4550 (30 mg/kg) and Vehicle. After treatment, the tumors were collected, and RNA was extracted for RNA sequencing.