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A renaissance in targeting the PI3K/AKT/mTOR pathway

Sarah E Conduit1, Neil Vasan2, Jennifer R Brown3

  • 1UCL Cancer Institute, University College London, London, UK. s.conduit@ucl.ac.uk.

Nature Reviews. Drug Discovery
|March 30, 2026
PubMed

Insights

Targeting the PI3K/AKT/mTOR pathway offers therapeutic potential for cancer and immune disorders. Despite challenges like resistance, new strategies are revitalizing interest in modulating this crucial signaling pathway.

Area of Science:

  • Biochemistry
  • Pharmacology
  • Oncology

Background:

  • The phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is implicated in cancer, immune regulation, and genetic disorders.
  • This pathway is a validated drug target due to its significant role in cellular processes.
  • Despite approved agents, drug development faces hurdles including tolerability and resistance.

Purpose of the Study:

  • To review the challenges and successes in targeting the PI3K/AKT/mTOR pathway.
  • To highlight recent advancements and future directions in the therapeutic modulation of this signaling cascade.
  • To provide insights into overcoming resistance mechanisms and improving drug tolerability.

Main Methods:

  • Literature review of preclinical and clinical studies.
  • Analysis of pharmacological approaches and biological understanding of the PI3K/AKT/mTOR pathway.
  • Synthesis of current challenges and emerging strategies in pathway targeting.

Main Results:

  • The PI3K/AKT/mTOR pathway remains a promising target with significant therapeutic potential.
  • Overcoming drug resistance and improving tolerability are key areas of focus.
  • Novel pharmacological agents and combination therapies are under investigation.

Conclusions:

  • Renewed interest and confidence exist in therapeutically modulating PI3K/AKT/mTOR signaling.
  • Continued research is essential to fully exploit the therapeutic benefits of targeting this pathway.
  • Improved biological and clinical understanding will drive future drug development efforts.

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