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PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer

Antonino Glaviano1, Aaron S C Foo2, Hiu Y Lam3,4

  • 1Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, 90123, Palermo, Italy.

Molecular Cancer
|August 18, 2023
PubMed

Insights

The PI3K/AKT/mTOR (PAM) pathway drives cancer growth and treatment resistance. Inhibitors targeting this pathway show promise in clinical trials for overcoming resistance, though resistance mechanisms persist.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The PI3K/AKT/mTOR (PAM) pathway regulates cell survival, growth, and progression.
  • Dysregulation of the PAM axis is common in human cancers and linked to treatment resistance.
  • Hyperactivity of PI3K, PTEN loss, and AKT gain-of-function drive cancer progression and resistance.

Purpose of the Study:

  • To review major dysregulations of the PAM pathway in cancer.
  • To discuss the efficacy of PAM inhibitors in clinical trials for overcoming treatment resistance.
  • To explore resistance mechanisms to PAM-targeted therapies, including roles in immunology and immunotherapy.

Main Methods:

  • Literature review of dysregulations in the PAM signaling pathway in cancer.
  • Analysis of clinical trial data for PI3K, AKT, and mTOR inhibitors as monotherapy and combination treatments.
  • Examination of mechanisms of resistance to PAM-targeted therapies.

Main Results:

  • The PAM axis is frequently activated in cancer and associated with resistance to therapies.
  • PAM inhibitors show potential in clinical trials, both alone and with other agents, to overcome resistance.
  • Understanding resistance mechanisms is crucial for effective cancer treatment strategies.

Conclusions:

  • Targeting the PAM pathway is a key strategy in cancer therapy development.
  • Further research into resistance mechanisms, including the interplay with immunology and immunotherapy, is essential.
  • Combination therapies and novel strategies are needed to overcome PAM-driven resistance in cancer.
Keywords:
AKT inhibitorsATP-competitive mTOR inhibitorsAllosteric mTOR inhibitorsBi-steric mTOR inhibitorsCancerDual PI3K/mTOR inhibitorsIsoform-specific PI3K inhibitorsPDK1 inhibitorsPI3K/AKT/mTORC pathwayPan PI3K inhibitors

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