PAK and PI3K pathway activation confers resistance to KRASG12C inhibitor sotorasib

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Updated: Aug 23, 2025

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Chien-Hui Chan1, Li-Wen Chiou1, Tsai-Yu Lee1

  • 1Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.

British Journal of Cancer
|November 2, 2022
PubMed
Abstract

Insights

Resistance to KRAS G12C inhibitors like sotorasib can be overcome. Targeting cell-matrix adhesion pathways, specifically p21-activated kinases (PAKs) and PI3K/AKT, alongside sotorasib, enhances treatment efficacy in KRAS G12C mutant cancers.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • KRAS is a key oncogene in human cancers, with KRAS G12C mutations being a significant target.
  • Covalent inhibitors targeting KRAS G12C show promise but face challenges from primary and acquired resistance.
  • Understanding resistance mechanisms is crucial for improving therapeutic strategies.

Purpose of the Study:

  • To investigate the signaling pathways driving resistance to sotorasib, a KRAS G12C inhibitor.
  • To identify potential therapeutic targets that can overcome sotorasib resistance.
  • To explore the interplay between resistance pathways and their impact on cancer cell viability.

Main Methods:

  • Established sotorasib-resistant cancer cell lines for mechanistic studies.
  • Analyzed activated signaling pathways, including MAPK and PI3K/AKT, in resistant cells.
  • Utilized specific inhibitors (FRAX597, FRAX486, alpelisib) and genetic manipulations (PTEN knockdown) to probe pathway functions.

Main Results:

  • Sotorasib-resistant cells showed increased cell-matrix adhesion and activated p21-activated kinases (PAKs).
  • Activated PAKs promoted MAPK pathway signaling, contributing to resistance.
  • Constitutive activation of the PI3K/AKT pathway was observed, with PI3K/PAK pathways forming a mutual regulatory loop.
  • Combined inhibition of PAK or PI3K with sotorasib synergistically reduced cancer cell viability.

Conclusions:

  • Cell-matrix interaction-dependent activation of PAK is a key mechanism of sotorasib resistance.
  • This resistance is mediated through the activation of MAPK and PI3K pathways.
  • Targeting PAK and PI3K pathways in combination with sotorasib offers a promising strategy to overcome resistance in KRAS G12C mutant cancers.

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