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Small Molecule SOS1 Agonists Modulate MAPK and PI3K Signaling via Independent Cellular Responses

Denis T Akan1, Jennifer E Howes1, Jiqing Sai1

  • 1Department of Biochemistry , Vanderbilt University School of Medicine , 2215 Garland Avenue, 607 Light Hall , Nashville , Tennessee 37232-0146 , United States.

ACS Chemical Biology
|February 9, 2019
PubMed

Insights

Targeting SOS1 with novel agonists modulates RAS signaling, impacting both MAPK and PI3K pathways. Researchers identified a potent SOS1 agonist with rapid, on-target effects, advancing therapeutic strategies for RAS-driven cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Activating RAS mutations drive oncogenesis via MAPK and PI3K pathways.
  • Targeting RAS signaling pathways is a key therapeutic strategy.
  • SOS1 (Son of Sevenless homolog 1) is a guanine nucleotide exchange factor that modulates RAS activity.

Purpose of the Study:

  • To investigate the mechanistic link between SOS1 agonist activity and downstream signaling modulation.
  • To explore the therapeutic potential of SOS1 agonists in RAS-driven oncogenesis.
  • To identify potent SOS1 agonists with specific on-target effects.

Main Methods:

  • Utilized chemically distinct SOS1 agonist compounds.
  • Employed CRISPR/Cas9 gene-editing to generate SOS1 knockout cells.
  • Analyzed ERK and AKT phosphorylation levels to assess pathway modulation.

Main Results:

  • SOS1 agonists demonstrated biphasic modulation of ERK phosphorylation and simultaneous inhibition of AKT phosphorylation.
  • Distinct SOS1 agonists were used to confirm mechanistic links in signaling effects.
  • A potent SOS1 agonist was identified, eliciting rapid on-target effects at low concentrations.

Conclusions:

  • SOS1 agonists can simultaneously modulate MAPK and PI3K signaling pathways.
  • CRISPR/Cas9-generated SOS1 knockout cells aided in elucidating on-target effects.
  • Findings support the further definition of SOS1 agonists for therapeutic utility in RAS-driven cancers.

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