Data from RIT1<sup>M90I</sup> Is a Driver of Lung Adenocarcinoma Tumorigenesis and Resistance to Targeted Therapy

<div>Abstract<p>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 <i>RIT1</i> 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 <i>in vitro</i> and <i>in vivo</i> models harboring RIT1 alterations. In this study, we generated a murine model of RIT1<sup>M90I</sup>-mutant lung cancer. RIT1<sup>M90I</sup> 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 <i>ex vivo</i> and <i>in vivo</i>. Finally, RIT1<sup>M90I</sup> drove resistance to the KRAS<sup>G12C</sup> inhibitor, divarasib, and the combination with migoprotafib reverted this phenotype. Together, these data show that RIT1<sup>M90I</sup> is a <i>bona fide</i> 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.</p>Significance:<p>Development of a mouse model of RIT1<sup>M90I</sup>-altered non-small cell lung cancer reveals that RIT1<sup>M90I</sup> is a driver of lung tumorigenesis and that RIT1-mutated tumors are sensitive to MAPK pathway inhibitors.</p><p><a href="https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-25-1989" target="_blank"><i>See related commentary by Wu and Vaishnavi, p. 3186</i></a></p><p><a href="https://aacrjournals.org/cancerres/article-abstract/doi/10.1158/0008-5472.CAN-24-3819" target="_blank"><i>See related article by Mozzarelli et al., p. 3196</i></a></p></div>