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Cell Type-specific Adaptive Signaling Responses to KRASG12C Inhibition.

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KRAS G12C inhibitors face resistance from bypass signaling. This study reveals cell-type-specific adaptive responses, identifying ERBB2/3 in epithelial cells and FGFR1/AXL in mesenchymal cells as key targets for combination therapies and patient selection.

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Area of Science:

  • Oncology
  • Molecular Biology
  • Signaling Pathways

Background:

  • KRAS G12C inhibitors (KRASi) target specific tumors but face adaptive resistance via bypass signaling.
  • Understanding resistance mechanisms is crucial for improving KRASi efficacy and developing predictive biomarkers.

Purpose of the Study:

  • To investigate cell type-specific signaling responses to KRAS G12C inhibition.
  • To identify mechanisms of adaptive resistance and potential combination strategies.
  • To explore biomarkers for patient enrichment in KRAS G12C-driven cancers.

Main Methods:

  • Mass spectrometry-based phosphoproteomics in KRAS G12C cell lines treated with ARS-1620.
  • Comparative analysis of proteome and phosphoproteome data.
  • Examination of gene expression patterns in cell lines and human lung tumor tissues.

Main Results:

  • Epithelial cells showed compensatory ERBB2/3 signaling upon KRASi, suggesting responsiveness to SHP2/SOS1 co-inhibition.
  • Mesenchymal cells displayed high basal FGFR or AXL signaling, with FGFR inhibition impacting ERK/mTOR and AXL impacting PI3K pathways.
  • KRAS G12C tumors exhibited cell type-specific signaling profiles: ERBB2/3 in epithelial, FGFR1/AXL in mesenchymal.

Conclusions:

  • Phosphoproteomic analysis revealed cell type-adaptive resistance mechanisms to KRAS inhibitors.
  • ERBB2/3 signaling markers in epithelial subtypes and FGFR1/AXL in mesenchymal subtypes are potential targets for combination therapy.
  • These findings support patient enrichment strategies based on cell type-specific signaling for KRASi treatment.