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Multiomic characterization of oncogenic signaling mediated by wild-type and mutant RIT1

April Lo1,2, Kristin Holmes1, Shriya Kamlapurkar1

  • 1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.

Science Signaling
|November 30, 2021
PubMed

Insights

RAS signaling is crucial in lung cancer. This study reveals that RIT1 gene amplification, not just mutation, can drive cancer by promoting RAS signaling and epithelial-to-mesenchymal transition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Aberrant RAS GTPase activation is common in lung adenocarcinoma, with KRAS mutations in ~30% of cases.
  • RAS family GTPase RIT1 mutations and amplifications have been identified in lung adenocarcinomas.

Purpose of the Study:

  • To investigate biological pathways regulated by RIT1.
  • To understand RIT1's relationship with the oncogenic KRAS network.

Main Methods:

  • Quantitative proteomic, phosphoproteomic, and transcriptomic profiling.
  • Ectopic expression of wild-type and cancer-associated variants of RIT1 and KRAS in isogenic lung epithelial cells.

Main Results:

  • Both mutant KRAS and mutant RIT1 activated canonical RAS signaling pathways.
  • Overexpression of wild-type RIT1 mimicked aspects of oncogenic RIT1 and KRAS, including epithelial-to-mesenchymal transition induction.
  • RIT1 protein abundance appears critical for its pathogenic role.

Conclusions:

  • Chromosomal amplification of wild-type RIT1 may contribute to tumorigenesis in lung and other cancers.
  • RIT1 abundance is a significant factor in its oncogenic function, alongside mutations.

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