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Updated: Nov 10, 2025

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Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Sarah Christine Elisabeth Wright1,2, Natali Vasilevski1,2, Violeta Serra3

  • 1Curtin Medical School, Faculty of Health Sciences, Curtin University, Bentley 6102, Australia.

Cancers
|April 3, 2021
PubMed

Insights

The phosphatidylinositol-3-kinase (PI3K) pathway is crucial in cancer, but PI3K inhibitors face resistance. This review explores adaptive responses causing resistance and strategies to overcome them for better cancer therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Signaling

Background:

  • The phosphatidylinositol-3-kinase (PI3K) pathway regulates critical cellular functions like growth and survival.
  • Hyperactivation of the PI3K pathway is common in human cancers and linked to tumor progression.
  • PI3K pathway activation can limit the efficacy of anti-cancer agents, necessitating PI3K inhibitors.

Purpose of the Study:

  • To review common adaptive responses leading to PI3K pathway reactivation.
  • To discuss mechanisms of therapy resistance associated with PI3K pathway reactivation.
  • To explore strategies for overcoming PI3K inhibitor resistance.

Main Methods:

  • Literature review of adaptive responses in PI3K pathway signaling.
  • Analysis of compensatory mechanisms driving therapy resistance.
  • Examination of cellular plasticity's role in PI3K inhibitor resistance.

Main Results:

  • Identified common adaptive responses that reactivate the PI3K pathway.
  • Detailed mechanisms by which pathway reactivation leads to therapy resistance.
  • Highlighted the impact of cellular plasticity on PI3K inhibitor effectiveness.

Conclusions:

  • PI3K pathway reactivation through compensatory mechanisms limits the clinical effectiveness of PI3K inhibitors.
  • Understanding adaptive responses and cellular plasticity is key to developing strategies to overcome resistance.
  • Targeted strategies are needed to improve PI3K inhibitor efficacy in cancer treatment.
Keywords:
PI3K pathwayPI3K pathway inhibitorsmechanisms of resistance

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