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Updated: Sep 16, 2025

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
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Published on: July 17, 2019

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Genetic and oncogenic features of RASGRF fusions

Sreya Das1,2,3, Daniel S Lenchner1,2,3, Ellen Jaeger4

  • 1Department of Internal Medicine, Section of Medical Oncology, Yale School of Medicine, New Haven, CT, USA.

NPJ Precision Oncology
|July 4, 2025
PubMed

Insights

RASGRF fusions are newly identified oncogenic drivers in cancers like lung and pancreatic cancer. These fusions activate the RAS pathway and may be targeted by MAPK inhibitors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Targeted therapies are revolutionizing cancer treatment by focusing on specific oncogenic drivers.
  • RASGRF1 and RASGRF2 are guanine exchange factors (GEFs) that activate RAS signaling, but their role in cancer is not fully understood.

Purpose of the Study:

  • To investigate the prevalence, genetic diversity, and oncogenic mechanisms of RASGRF1 and RASGRF2 fusions in human malignancies.
  • To explore the therapeutic potential of targeting RASGRF fusions.

Main Methods:

  • Analysis of RNA-sequencing data from a large, real-world database of diverse human tumors.
  • Functional assays to assess the transforming activity and oncogenic mechanisms of identified RASGRF fusions.

Main Results:

  • Identified 40 tumors with RASGRF1/2 rearrangements, with half occurring in non-small cell lung carcinoma (NSCLC), pancreatic cancer, and melanoma.
  • RASGRF fusions were enriched in tumors lacking other known driver alterations.
  • Transmembrane partners and loss of N-terminal domains (PH1 and DH) in RASGRF fusions enhanced RAS activation and transforming activity.
  • Loss of the PH1 domain alone was insufficient for cellular transformation.

Conclusions:

  • RASGRF fusions represent a novel class of oncogenic drivers with diverse tissue distribution and structural variations.
  • These fusions activate oncogenic signaling pathways, particularly through enhanced RAS activation.
  • RASGRF fusions are potential therapeutic targets, as cancer models exhibit sensitivity to MAPK pathway inhibition.

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