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Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell

Madlaina Breuleux1, Matthieu Klopfenstein, Christine Stephan

  • 1Novartis Pharma AG, Novartis Institutes for Biomedical Research, Oncology, Basel, Switzerland.

Molecular Cancer Therapeutics
|April 18, 2009
PubMed

Insights

mTORC1 inhibitors like RAD001 show antitumor activity, but resistance exists. Rictor, not raptor, influences AKT phosphorylation, impacting cancer cell response to mTORC1 inhibition.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Mammalian target of rapamycin (mTOR) is crucial for cancer progression.
  • RAD001 (everolimus) is an mTORC1 inhibitor with antitumor effects, but some tumors are resistant.
  • mTORC1 inhibition can paradoxically increase AKT phosphorylation, potentially reducing efficacy.

Purpose of the Study:

  • To investigate the roles of raptor and rictor in human cancer cell responses to RAD001.
  • To determine if AKT S473 phosphorylation predicts response to mTORC1 inhibition.
  • To evaluate combination therapies targeting PI3K/mTOR.

Main Methods:

  • Utilized a large panel of human cancer cell lines.
  • Assessed basal and RAD001-induced AKT S473 phosphorylation and substrate phosphorylation.
  • Employed siRNA to deplete raptor and rictor.
  • Tested a dual PI3K/mTOR inhibitor (NVP-BEZ235).

Main Results:

  • Basal AKT S473 phosphorylation correlated with antiproliferative response to RAD001.
  • RAD001-induced AKT S473 phosphorylation did not correlate with response.
  • Raptor depletion mimicked RAD001's effect on AKT phosphorylation.
  • Rictor downregulation attenuated RAD001-induced AKT S473 phosphorylation.
  • Dual PI3K/mTOR inhibition showed greater effects than mTORC1 inhibition alone.

Conclusions:

  • Rictor, not raptor, modulates AKT S473 phosphorylation during mTORC1 inhibition.
  • Predicting cellular response to mTORC1 inhibitors based solely on AKT phosphorylation is unreliable.
  • Combined PI3K/mTOR inhibition may offer enhanced therapeutic benefits in cancer treatment.

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