RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy.

RIT1 is a RAS-family GTPase that is mutated in 2.4% and amplified in up to 14% of lung adenocarcinoma patients. Yet, the oncogenic potential of RIT1 in the lungs has not been fully established. Consequently, patients with RIT1 alterations are considered "oncogene-negative" and are not eligible for any targeted therapy in the clinic. The role of RIT1 in cancer has been historically understudied due to the lack of in vitro and in vivo models harboring RIT1 alterations. In this study, we generated a murine model of RIT1M90I-mutant lung cancer. RIT1M90I expression induced tumorigenesis in the lungs, and the tumors displayed histopathological features similar to lung adenocarcinoma in humans. An unbiased chemical compound screen leveraging this model revealed a sensitivity to inhibitors of the MAPK, PI3K, and cholesterol biosynthesis pathways in RIT1 mutant cell lines. The SHP2 inhibitor, migoprotafib, in combination with other MAPK pathway targeted therapies effectively suppressed the growth of RIT1 mutant cells ex vivo and in vivo. Finally, RIT1M90I drove resistance to the KRASG12C inhibitor, divarasib, and the combination with migoprotafib reverted this phenotype. Together, our data shows that RIT1M90I is a bona fide oncogenic driver of lung cancer and mediator of targeted therapy resistance as a co-occurring mutation and suggests that RIT1-altered cancer patients may benefit from combination treatments with a SHP2 inhibitor.