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Updated: May 8, 2026

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PI3K Regulates Wild-type RAS Signaling to Confer Resistance to KRAS Inhibition

Xiangyu Ge1,2,3, Jaffarguriqbal Singh1,4, Wenxue Li1,5

  • 1Yale Cancer Biology Institute, Yale University, West Haven, Connecticut.

Cancer Research
|May 7, 2026
PubMed

Insights

Phosphoinositide 3-kinase (PI3K) drives resistance to KRAS inhibitors in pancreatic cancer by activating wild-type RAS signaling. Inhibiting PI3K restores sensitivity to KRAS-targeted therapies in pancreatic ductal adenocarcinoma.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) heavily relies on oncogenic KRAS mutations.
  • Resistance to KRAS inhibitors is a significant challenge in PDAC treatment.
  • The role of PI3K in RAS signaling pathways, particularly in resistance, is not fully understood.

Purpose of the Study:

  • To investigate the role of PI3K in mediating resistance to KRAS inhibition in PDAC.
  • To elucidate the molecular mechanisms by which PI3K contributes to KRAS inhibitor resistance.
  • To explore the therapeutic potential of combining PI3K and KRAS inhibitors for PDAC treatment.

Main Methods:

  • Proximity labeling
  • CRISPR screening
  • Live-cell imaging
  • Functional assays
  • Cell-based experiments

Main Results:

  • PI3K activates wild-type RAS signaling upstream of KRAS effectors, contributing to resistance.
  • PI3K facilitates GAB1 recruitment to the plasma membrane, assembling RAS signaling complexes.
  • RAS signaling activation is dependent on EGFR/SHP2/SOS1.
  • PI3K inhibition enhances PDAC cell sensitivity to KRAS inhibitors, including in cells with PIK3CA mutations.

Conclusions:

  • PI3K plays a critical role in driving resistance to KRAS inhibition in PDAC.
  • PI3K-mediated activation of wild-type RAS signaling is a key mechanism of resistance.
  • Targeting PI3K in combination with KRAS inhibitors offers a promising therapeutic strategy for PDAC.

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