Metformin-sensitized NSCLC cells to osimertinib via AMPK-dependent autophagy inhibition

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Hengyi Chen1, Caiyu Lin1, Conghua Lu1

  • 1Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China.

The Clinical Respiratory Journal
|September 29, 2019
PubMed
Abstract

Insights

Metformin enhances sensitivity to osimertinib in non-small-cell lung cancer (NSCLC) by inhibiting autophagy. This occurs through metformin-induced AMPK activation, which reduces pro-survival autophagy in NSCLC cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Osimertinib, a third-generation EGFR inhibitor, shows promise for advanced non-small-cell lung cancer (NSCLC).
  • Osimertinib treatment can activate pro-survival autophagy in NSCLC cells, potentially limiting its efficacy.
  • Understanding and modulating this autophagy is crucial for improving NSCLC treatment outcomes.

Purpose of the Study:

  • To investigate the role of osimertinib-induced autophagy in NSCLC.
  • To determine if metformin can modulate autophagy and enhance sensitivity to osimertinib.
  • To elucidate the underlying molecular mechanisms of metformin's action.

Main Methods:

  • In vitro and in vivo experiments were conducted.
  • Cell viability, proliferation, and invasion assays were performed.
  • Western blot analysis and siRNA techniques were utilized to study molecular pathways.

Main Results:

  • Osimertinib treatment induced pro-survival autophagy in NSCLC cell lines (H1975 and PC-9GR).
  • Metformin sensitized these cells to osimertinib by inhibiting autophagy.
  • Metformin's mechanism involves time-dependent activation of AMPK, which suppresses autophagy.

Conclusions:

  • Metformin effectively inhibits autophagy in NSCLC cells.
  • Metformin enhances the therapeutic sensitivity to osimertinib.
  • AMPK activation is the key mechanism by which metformin modulates autophagy and improves osimertinib efficacy.
Keywords:
AMPKautophagymetforminosimertinibsensitivity

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