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An mTOR feedback loop mediates the 'flare' ('rebound') response to MET tyrosine kinase inhibition

D M Altintas1, M Cerqua2, A De Laurentiis3

  • 1IFOM ETS - The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139, Milano, Italy. dogus.altintas@ifom.eu.

Scientific Reports
|January 25, 2023
PubMed

Insights

Targeted therapy for MET oncogene-driven cancers can cause a rebound effect. This study reveals a feedback loop involving the AKT/mTOR pathway that drives this "MET burst," suggesting mTOR inhibitors could prevent it.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Targeted therapies, particularly MET tyrosine kinase inhibitors, are crucial for treating cancers with MET oncogene alterations.
  • A significant limitation is the 'flare' or 'rebound' effect, characterized by increased cancer cell proliferation after treatment cessation.
  • The underlying molecular mechanisms of this rebound phenomenon, termed the 'MET burst,' remain largely unknown.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving the 'MET burst' following MET tyrosine kinase receptor inhibition.
  • To identify potential therapeutic strategies to mitigate the 'flare effect' in MET-targeted therapy.

Main Methods:

  • Investigated the molecular pathways involved in MET oncogene rebound activation post-treatment.
  • Utilized in vitro models to analyze protein interactions and signaling cascades.
  • Focused on the role of the AKT/mTOR pathway and its downstream effectors.

Main Results:

  • Identified a positive feedback loop mediated by the AKT/mTOR pathway.
  • Demonstrated that this loop enhances MET translation via p70S6K and 4EBP1 activation.
  • Showed that mTOR-driven phosphorylation of PTP1B inactivates the tyrosine-phosphatase, leading to MET hyper-phosphorylation.

Conclusions:

  • The AKT/mTOR pathway is central to the 'MET burst' phenomenon.
  • mTOR inhibition presents a viable strategy to prevent the 'flare effect' in MET-targeted therapy.
  • These findings have potential implications for improving clinical management of patients undergoing MET-targeted treatment.

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