RIT1 as Novel Driver Oncogene in Lung Adenocarcinoma

Lung cancer is the most common cause of global cancer-related mortality, leading to more than one million deaths each year and adenocarcinoma is its most common histological type. Recently, molecularly targeted therapies have dramatically improved treatment for patients whose tumors harbor somatically activated oncogenes such as mutant EGFR. However, most lung adenocarcinomas either lack an identifiable driver oncogene, or harbor mutations in KRAS and are therefore still treated with conventional chemotherapy. Therefore, continued identification of oncogenic driver genes in “oncogene-negative” lung adenocarcinoma cases may allow further patient stratification and the development of new targeted therapies. Our proposed studies are highly significant, as we will focus on elucidating the functional importance of a novel oncogene driver in lung adenocarcinoma, the RIT1 (Ras-like in all tissues) GTPase. Using whole-exome sequence analysis on a subgroup of ‘oncogenenegative’ tumors we recently identified somatic RIT1 mutations in ~2.5% of lung adenocarcinoma cases. Importantly, RIT1 mutations were found to be mutually exclusive with all previously known lung adenocarcinoma oncogenes, being more prevalent in male smokers, and thus likely to be over represented in Kentucky patients. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo. The central hypothesis driving this proposal is that somatic RIT1 mutations serve as novel driver mutations in a subset of lung adenocarcinomas. The long-term goal of our studies is to elucidate the functional importance of RIT1 in lung adenocarcinoma with the goal of creating novel avenues for therapeutic intervention.