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Role of mesenchymal-epithelial transition amplification in resistance to anti-epidermal growth factor receptor agents

Raffaele Califano1, Floriana Morgillo1, Ramon Andrade De Mello1

  • 11 Cancer Research UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester M20 4BX, UK ; 2 Department of Medical Oncology, University Hospital of South Manchester NHS Foundation Trust, Manchester M23 9LT, UK ; 3 Dipartimento di internistica clinica e sperimentale "F. Magrassi e A. Lanzara", Seconda Università degli studi di Napoli, Naples, Italy ; 4 Department of Biomedical Sciences and Medicine, University of Algarve, Faro 8005-139, Portugal ; 5 Department of Medical Oncology, Portuguese Oncology Institute, Porto 4200-072, Portugal ; 6 University of Athens School of Medicine, Athens, Greece.

Annals of Translational Medicine
|May 21, 2015
PubMed

Insights

Resistance to EGFR-TKIs in advanced non-small cell lung cancer is common. MET amplification is a key mechanism of acquired resistance, prompting research into combination therapies targeting both EGFR and MET pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are standard treatment for EGFR-mutant advanced non-small cell lung cancer (NSCLC).
  • Acquired resistance to EGFR-TKIs, typically within 9-12 months, limits long-term patient benefit.
  • While T790M mutation is the most frequent resistance mechanism, other pathways are implicated.

Purpose of the Study:

  • To review the role of MET amplification as a mechanism of acquired resistance to EGFR-TKIs in NSCLC.
  • To discuss therapeutic strategies for overcoming MET-mediated resistance.

Main Methods:

  • Literature review of preclinical and clinical studies.
  • Analysis of mechanisms of acquired resistance to EGFR-TKIs.
  • Evaluation of combination therapies targeting EGFR and MET pathways.

Main Results:

  • MET gene amplification is a significant mechanism of acquired resistance to EGFR-TKIs in NSCLC.
  • MET amplification, though rare as a primary resistance event, is frequently observed in acquired resistance.
  • Combination strategies targeting both EGFR and MET are under investigation to overcome this resistance.

Conclusions:

  • MET amplification is a critical determinant of acquired resistance to EGFR-TKIs in NSCLC.
  • Targeting MET, particularly in combination with EGFR inhibitors, holds promise for overcoming resistance and improving patient outcomes.
Keywords:
Epidermal growth factor receptor (EGFR)crizotinibmesenchymal-epithelial transition (MET)onartuzumabtivantinib

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