Activation of IGF1R/p110β/AKT/mTOR confers resistance to α-specific PI3K inhibition

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Cedric Leroy1,2, Pedro Ramos1,2, Karen Cornille1

  • 1Friedrich Miescher Institute for Biomedical Research, Maulbeerstraße 66, 4058, Basel, Switzerland.

Breast Cancer Research : BCR
|April 7, 2016
PubMed
Abstract

Insights

Targeting the PI3K pathway in breast cancer shows limited success. A new study reveals that the IGF1R/p110β/AKT/mTOR axis drives resistance to BYL719, suggesting combination therapies for PIK3CA-mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Phosphoinositide 3-kinase (PI3K) pathway hyperactivation is common in cancers, particularly 70% of breast cancers.
  • PI3K pathway inhibitors are under clinical investigation, but their efficacy as single agents is limited.
  • Understanding resistance mechanisms is crucial for improving therapeutic outcomes.

Purpose of the Study:

  • To investigate molecular mechanisms of resistance to the p110α-selective PI3K inhibitor BYL719.
  • To identify signaling pathways involved in acquired resistance to BYL719 in breast cancer.

Main Methods:

  • Development of BYL719-resistant breast cancer cell lines.
  • Unbiased phosphotyrosine proteomics to analyze signaling pathway changes.
  • Pharmacological inhibition to characterize resistance mechanisms.

Main Results:

  • Resistant cells showed increased phosphorylation of IGF1R, IRS1/IRS2, and p85.
  • An IGF1R/IRS/p85/p110β complex was identified, activating AKT/mTOR/S6K and conferring resistance.
  • Inhibition of this complex components restored sensitivity to BYL719.

Conclusions:

  • The IGF1R/p110β/AKT/mTOR axis drives resistance to BYL719 in PIK3CA-mutant breast cancers.
  • Combined targeting of p110α with IGF1R or p110β is a potential therapeutic strategy.
  • This study provides a rationale for combination therapies in PIK3CA-mutant breast tumors.
Keywords:
Breast cancerPhosphatidylinositol 3-kinaseResistancep110αp110β

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