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Oncogenic RAS isoforms show a hierarchical requirement for the guanine nucleotide exchange factor SOS2 to mediate

Erin Sheffels1, Nancy E Sealover1, Chenyue Wang1

  • 1Department of Pharmacology and Molecular Therapeutics, Uniformed Services University of the Health Sciences, Bethesda, MD 20814, USA.

Science Signaling
|September 6, 2018
PubMed

Insights

SOS2 is crucial for mutant KRAS-driven cancer growth by activating PI3K signaling. Targeting SOS2 and PI3K offers new therapeutic strategies for KRAS-mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • Activating mutations in RAS family genes (HRAS, NRAS, KRAS) are common in cancers.
  • Wild-type RAS cooperates with mutant RAS, driving cell proliferation and transformation.
  • The guanine nucleotide exchange factor (GEF) SOS1 is known to mediate KRAS-driven proliferation, but SOS2's role is less understood.

Purpose of the Study:

  • To investigate the role of SOS2 in RAS-driven oncogenesis.
  • To elucidate the signaling pathways downstream of SOS2 in mediating cellular transformation.
  • To identify potential therapeutic targets for KRAS-mutant cancers.

Main Methods:

  • Utilized mouse embryonic fibroblasts (MEFs) with and without SOS2.
  • Employed CRISPR/Cas9 gene editing to delete SOS2.
  • Assessed cellular transformation, epidermal growth factor (EGF)-dependent signaling, and AKT phosphorylation.
  • Used pharmacological inhibitors and expression of constitutively activated PI3K.
  • Investigated tumor cell lines in 3D culture systems.

Main Results:

  • SOS2 is essential for mutant KRAS-driven, but not HRAS-driven, cellular transformation in MEFs.
  • SOS2 deletion reduced EGF-dependent activation of HRAS and AKT phosphorylation in cells with mutant RAS.
  • A hierarchical requirement for phosphoinositide 3-kinase (PI3K) signaling was observed, mirroring SOS2's role.
  • KRAS-driven transformation depended on SOS2's GEF activity and could be restored by activated PI3K in SOS2-deficient cells.
  • SOS2 deletion in human KRAS-mutant tumor cells reduced AKT phosphorylation and, with MEK inhibition, reverted the transformed phenotype.

Conclusions:

  • SOS2-dependent PI3K signaling is a key mediator of mutant KRAS-driven cellular transformation.
  • SOS2 represents a potential therapeutic target in KRAS-driven cancers.
  • The study highlights the importance of SOS2 in RAS oncogenesis and suggests targeting the SOS2-PI3K axis.

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