RIT1M90I Is a Driver of Lung Adenocarcinoma Tumorigenesis and Resistance to Targeted Therapy.

RIT1 is a RAS-family guanosine triphosphatase that is mutated in 2.4% and amplified in up to 14% of patients with lung adenocarcinoma. 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 histopathologic 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, these data show that RIT1M90I is a bona fide oncogenic driver of lung cancer and a mediator of targeted therapy resistance as a co-occurring mutation and suggest that patients with RIT1-altered cancer may benefit from combination treatments with an SHP2 inhibitor. SIGNIFICANCE: Development of a mouse model of RIT1M90I-altered non-small cell lung cancer reveals that RIT1M90I is a driver of lung tumorigenesis and that RIT1-mutated tumors are sensitive to MAPK pathway inhibitors. See related commentary by Wu and Vaishnavi, p. 3186 See related article by Mozzarelli et al., p. 3196.