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Akt-induced endocrine therapy resistance is reversed by inhibition of mTOR signaling

M Beeram1, Q-T N Tan, R R Tekmal

  • 1Department of Medical Oncology, University of Texas Health Science Center, San Antonio, TX 78229, USA.

Annals of Oncology : Official Journal of the European Society for Medical Oncology
|August 19, 2007
PubMed
Abstract

Insights

High Akt activity causes resistance to endocrine therapies in breast cancer. Combining mTOR inhibitors with antiestrogens like Letrozole or Fulvestrant can reverse this resistance, restoring treatment effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • Endocrine therapy resistance is a significant challenge in breast cancer treatment.
  • The Phosphatidylinositol-3-OH kinase (PI3K)/Protein kinase B (Akt/PKB) pathway is implicated in therapy response.
  • Understanding Akt's role in modulating treatment response is clinically relevant.

Purpose of the Study:

  • To investigate the effects of high Akt activity on breast cancer cell response to endocrine therapies.
  • To explore mechanisms of Akt-induced resistance to endocrine agents.
  • To evaluate the potential of combining mTOR inhibitors with endocrine therapies to overcome resistance.

Main Methods:

  • Utilized an in vitro model of breast cancer cells.
  • Assessed cellular response to aromatase inhibitor Letrozole and selective estrogen receptor down-regulator Fulvestrant.
  • Investigated the impact of cotreatment with an mTOR inhibitor (RAD-001) on resistant cells.

Main Results:

  • High Akt activity conferred resistance to Letrozole and Fulvestrant.
  • Akt-induced resistance involved altered cell cycle and apoptotic responses, not ERalpha inhibition failure.
  • Cotreatment with RAD-001 restored sensitivity to Letrozole and Fulvestrant in resistant cells.

Conclusions:

  • Cotreatment with mTOR inhibitors and antiestrogens (Letrozole or Fulvestrant) reverses Akt-mediated resistance.
  • Concurrent inhibition of Estrogen Receptor (ER) and mTOR is a viable strategy to overcome growth factor-induced resistance.
  • Findings have implications for optimizing clinical development of endocrine and mTOR inhibitor therapies in breast cancer.

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