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Targeting the PI3K/PTEN/AKT/mTOR Pathway in Treatment of Sarcoma Cell Lines

Hui Jun Lim1, Xiaochun Wang1, Philip Crowe1

  • 1Sarcoma and Nano-oncology Group, Adult Cancer Program, Lowy Cancer Research Centre, Department of Medical Oncology and Surgery, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Randwick, NSW, Australia.

Anticancer Research
|October 30, 2016
PubMed
Abstract

Insights

Sarcoma cell lines rarely have PTEN mutations, and PI3K/Akt/mTOR pathway activation is independent of PTEN status. All tested sarcoma cell lines responded to mTOR inhibition with ridaforolimus.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Sarcoma has a poor prognosis, necessitating targeted therapies.
  • The PI3K/Akt/mTOR pathway is frequently dysregulated in cancers, often due to loss of PTEN.
  • Comprehensive studies on PTEN status and PI3K/Akt/mTOR pathway activation in sarcoma are lacking.

Purpose of the Study:

  • To characterize PTEN and Akt expression in sarcoma cell lines.
  • To investigate the efficacy of mTOR inhibition using ridaforolimus in sarcoma.

Main Methods:

  • PTEN gene sequencing (Sanger).
  • Western blot analysis for PTEN, total Akt (tAkt), and phosphorylated Akt (pAkt).
  • Crystal violet assay for antiproliferative effects and Chou & Talalay's isobologram for drug synergy.

Main Results:

  • PTEN mutations were rare; one GCT cell line showed a missense mutation with loss of PTEN protein.
  • Constitutive PI3K/Akt/mTOR pathway activation was observed, independent of wild-type PTEN status.
  • All sarcoma cell lines were sensitive to ridaforolimus, with IC50 values in the nanomolar range.

Conclusions:

  • PTEN mutations are uncommon in sarcoma cell lines.
  • Constitutive PI3K/Akt/mTOR activation in sarcoma is not solely dependent on PTEN status.
  • Ridaforolimus demonstrates potential as a targeted therapy for sarcoma.
Keywords:
PI3K/PTEN/Akt/mTOR pathwayPTEN expressionSarcomatargeted therapy

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