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Role of PI3K/Akt/mTOR pathway in mediating endocrine resistance: concept to clinic

Aglaia Skolariki1, Jamie D'Costa1, Martin Little2

  • 1Department of Oncology, University of Oxford, Churchill Hospital, OX3 7LE Oxford, UK.

Exploration of Targeted Anti-Tumor Therapy
|September 1, 2022
PubMed

Insights

Estrogen receptor-positive breast cancer often becomes resistant to endocrine therapy. The PI3K/Akt/mTOR pathway is a key factor in this resistance, leading to new targeted treatments for advanced disease.

Area of Science:

  • Oncology
  • Pharmacology
  • Molecular Biology

Background:

  • Most breast cancers are estrogen receptor (ER)-positive, making endocrine therapy a primary treatment.
  • Drug resistance frequently develops, necessitating research into alternative therapeutic strategies.
  • The PI3K/Akt/mTOR signaling pathway is implicated in treatment failure for ER-positive breast cancer.

Purpose of the Study:

  • To review preclinical and clinical evidence supporting the PI3K/Akt/mTOR pathway as a target in endocrine-resistant breast cancer.
  • To discuss the development and approval of PI3K and mTOR inhibitors for advanced ER-positive breast cancer.
  • To explore future research directions in targeting this pathway.

Main Methods:

  • Review of preclinical studies investigating the PI3K/Akt/mTOR axis in breast cancer models.
  • Analysis of clinical trial data for patients with advanced ER-positive breast cancer treated with PI3K/mTOR inhibitors.
  • Synthesis of existing literature on endocrine therapy resistance mechanisms.

Main Results:

  • Preclinical data established the PI3K/Akt/mTOR pathway as a critical mediator of resistance to endocrine therapy.
  • Clinical trials demonstrated efficacy of PI3K and mTOR inhibitors in patients with relapsed or refractory advanced ER-positive breast cancer.
  • These findings led to the approval of targeted agents for this patient population.

Conclusions:

  • The PI3K/Akt/mTOR pathway is a validated therapeutic target in advanced ER-positive breast cancer.
  • Targeted inhibition of this axis offers a new treatment paradigm for patients resistant to standard endocrine therapy.
  • Further research is warranted to optimize treatment strategies and overcome resistance to PI3K/mTOR inhibitors.
Keywords:
Breast cancerPI3K/Akt/mTOR pathwayendocrine therapy

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