Abstract 6849: RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy

Abstract 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 is not completely understood. Many patients with RIT1 alterations are considered ‘oncogene-negative’, hence they 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 the first murine model of RIT1M90I-mutant lung cancer. We found that RIT1M90I was tumorigenic in the lungs and the tumors displayed histopathological features similar to lung adenocarcinoma. We leveraged this new model to assess both ex vivo and in vivo sensitivity of RIT1 tumors to the SHP2 inhibitor, migoprotafib, in combination with other targeted therapies. Finally, we showed that RIT1M90I can also drive resistance to the KRASG12C inhibitor, divarasib, and that the combination with migoprotafib can revert this phenotype. Our data shows that RIT1M90I is a bona fide oncogenic driver of NSCLC and mediator of targeted therapy resistance as a co-occurring mutation. Taken together, our study suggests that RIT1-altered cancer patients may benefit from combination treatment with SHP2 inhibitor in the primary and resistance setting. Citation Format: Ashley DiMarco, Mirunalini Ravichandran, Jeffery Lau, Anthony Lima, Eva Lin, Julie Weng, Luca Gerosa, Pablo Saenz-Lopez Larracho, Thomas Hunsaker, Yang Xiao, Monika Mis, Charles Havnar, Kai Barck, Klara Totpal, Oded Foreman, Mark Merchant, Nicole Sodir, Danilo maddalo. RIT1M90I is a driver of lung adenocarcinoma tumorigenesis and resistance to targeted therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6849.