Discovery of Novel RASGRF2 Fusions as a Therapeutic Target in Lung Adenocarcinoma of Never or Light Smokers

Lung adenocarcinomas (LUADs) in never-smokers exhibit distinct molecular profiles from those of smokers, and their driver mutations are quite divergent. We aimed to evaluate the utility of RNA-seq for the molecular profiling of LUAD in Japanese never or light smokers. A hybridization capture-based RNA panel (TOP2-RNA) was used to confirm the validity of mutational and expression analyses of the panel in 122 Japanese LUAD cases. For the discovery cohort, 270 primary LUADs were molecularly profiled using TOP2-RNA. Whole transcriptome sequencing (WTS) was conducted for the samples without any oncogenic driver mutations. A risk score was developed using TOP2-RNA expression data to predict the prognosis of surgically resected LUAD. Driver oncogenes were identified in 180 cases (66.7%) of the discovery cohort. The frequency of MET ex14 skipping was high (12.6%) among cases without EGFR mutations. Actionable novel fusions of RDX-RASGRF1, PRKCI-RASGRF2, and OCLN-RASGRF2 were identified in three never-smoker cases by WTS. A functional assay identified that the expression of RASGRF fusions transformed the cells through phosphorylation of MEK, which was inhibited by cobimetinib treatment. High-risk patients defined by the risk score based on the four-gene signature had significantly worse RFS and OS for all stages and stage I patients in the discovery and validation cohorts. This study identified novel RASGRF1/2 fusions that might be targetable by MEK inhibitors. RNA-based molecular profiling could identify actionable mutations and assess the prognostic biomarkers for patient stratification to determine the optimal treatment based on the molecular profiling of individual LUAD cases.