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Active PI3K pathway causes an invasive phenotype which can be reversed or promoted by blocking the pathway at

Jeffrey J Wallin1, Jane Guan, Kyle A Edgar

  • 1Department of Cancer Signaling and Translational Oncology, Genentech, Inc., South San Francisco, California, USA. jwallin@gene.com

Plos One
|May 10, 2012
PubMed

Insights

Activating mutations in the PTEN/PI3K pathway drive cancer invasion. PI3K inhibitors reversed this effect, but Akt or mTOR inhibition worsened it, highlighting targeted therapy differences.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • The Phosphatase and Tensin homolog (PTEN)/Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway is frequently altered in various cancers.
  • Dysregulation of this pathway promotes tumorigenesis and metastasis, making it a key therapeutic target.

Purpose of the Study:

  • To investigate the direct cellular consequences of increased PTEN/PI3K pathway signaling.
  • To evaluate the efficacy of targeting different nodes within the PI3K pathway in a relevant cellular model.

Main Methods:

  • An activating mutation (H1047R) in PIK3CA was introduced into MCF10A human breast epithelial cells.
  • Cells were cultured in 3D to assess epithelial-mesenchymal transition (EMT) and invasion.
  • The effects of PI3K, Akt, and mTOR inhibitors were evaluated.

Main Results:

  • Endogenous PIK3CA mutation induced a significant epithelial-mesenchymal transition (EMT) and invasive phenotype.
  • Enhanced invasion was associated with increased PIP(3) production mediated by a S6K-IRS feedback loop.
  • Selective PI3K inhibitors effectively reversed the invasive phenotype.
  • Inhibition of Akt or mTOR paradoxically exacerbated invasion.

Conclusions:

  • Increased PTEN/PI3K pathway activity is a core driver of cancer cell invasion.
  • Targeting PI3K directly is effective in reversing invasion, while targeting downstream effectors like Akt or mTOR may have adverse outcomes.
  • Therapeutic strategies targeting the PI3K pathway require careful consideration of the specific node being inhibited to avoid promoting metastasis.

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