Publication date: Jul 05, 2025

The identification of recurrent oncogenic drivers has enabled targeted therapeutic strategies for subsets of non-small cell lung carcinoma (NSCLC) and other malignancies. Oncogenic fusions involving the RAS-activating guanine exchange factor (GEF) RASGRF1 are reported in multiple tumors, but their prevalence and genetic heterogeneity remain undefined. Here, we query RNA-seq data from a real-world database of diverse human malignancies and identify 40 tumors with rearrangements involving RASGRF1 or the related RASGRF2 predicted to generate chimeric proteins. Half of these fusions occur in NSCLC, pancreatic cancer, and melanoma and are enriched in tumors without other established driver alterations. A subset of RASGRF fusions contains transmembrane partners, and membrane localization enhances RAS activation and transforming activity. Loss of N-terminal PH1 and DH domains in RASGRF fusions also promotes transformation. Although some fusions lack the PH1 but not the DH domain, our functional assays indicate that loss of the PH1 domain alone is insufficient to drive cellular transformation. Our findings provide insights about the tissue distribution, structural diversity, and oncogenic mechanisms of RASGRF fusions. As cell models driven by these fusions are sensitive to MAPK pathway inhibition, oncogenic RASGRF fusions may represent a therapeutic target in rare molecular subsets of cancer.

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