Abstract 2726: Functional multiomic profiling identifies Aurora kinase inhibition as a therapeutic strategy in RIT1-mutant lung adenocarcinoma

Abstract

Abstract Treatment of lung cancer is evolving from standard cytotoxic to personalized treatment based on the molecular alterations unique to each patient’s tumor. In our recent work with TCGA and others, we identified somatic mutations in the gene encoding the RAS-related small GTPase, RIT1, in lung adenocarcinomas. In addition, somatic RIT1 mutations have also been identified in myeloid malignancies and germline RIT1 mutations are found in the developmental “RAS-opathy,” Noonan syndrome. In all these diseases, RIT1 mutations are mutually-exclusive with other RAS/MAPK pathway mutations, including mutations in EGFR, KRAS, and ALK. While our previous work demonstrated that gain-of-function RIT1 mutations induce activation of PI3K and MEK signaling, the specific effectors used by RIT1 to promote tumorigenesis are unknown. To genetically dissect the signaling pathways downstream of RIT1, KRAS, EGFR, and PIK3CA, we performed genome-wide CRISPR/Cas9 screens in four isogenic lung adenocarcinoma cell lines in which cell survival is dependent on the expression of the oncogene. Through integrative analysis of essential genes across the four cell lines, we identified synthetic lethal relationships unique and shared in each isogenic background. Among the dependencies identified was the requirement of aurora kinase pathway genes for survival of RIT1-mutant cells, raising the possibility of therapeutic aurora kinase inhibition in RIT1-positive tumors. To evaluate whether the dependence on Aurora kinases extended to small molecule inhibition, we performed a screen of 160 small molecules in clinical development or approved by the FDA. Consistent with our CRISPR/Cas9 results, we find that RIT1-mutant cells depend on Aurora kinase activity for survival. Interestingly, global phosphoproteomic profiling identified RIT1 regulation of an Aurora kinase-Haspin axis. Taken together these results identify a new arm of RIT1 signaling and nominate Aurora kinase inhibition as a potential therapeutic strategy in RIT1-mutated tumors. Citation Format: Athea Vichas, Naomi T. Nkinsi, Alice Berger. Functional multiomic profiling identifies Aurora kinase inhibition as a therapeutic strategy in RIT1-mutant lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2726.