MET inhibitors for targeted therapy of EGFR TKI-resistant lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have significantly improved outcomes for non-small cell lung cancer (NSCLC) patients with activating EGFR mutations.
• Acquired resistance, particularly through mechanisms like MET amplification, limits the long-term efficacy of EGFR-TKIs.
• MET amplification is implicated as a resistance mechanism not only to first- and second-generation EGFR-TKIs but also to third-generation inhibitors like osimertinib, especially in first-line settings.

Purpose of the Study:

• To investigate the role of MET amplification and/or protein hyperactivation as a resistance mechanism to third-generation EGFR-TKIs in NSCLC.
• To evaluate the potential of combination therapies for overcoming osimertinib resistance driven by MET alterations.

Main Methods:

• Review of preclinical and clinical studies examining resistance mechanisms to EGFR-TKIs.
• Analysis of data on MET amplification and/or protein hyperactivation in EGFR-mutant NSCLC.
• Evaluation of therapeutic strategies including combination treatments.

Main Results:

• MET amplification and/or protein hyperactivation is a key mechanism of acquired resistance to third-generation EGFR-TKIs, including osimertinib.
• EGFR-mutant NSCLCs with MET alterations that have relapsed from prior EGFR-TKI therapy may exhibit insensitivity to osimertinib monotherapy.

Conclusions:

• Combinatorial therapy involving osimertinib and a MET inhibitor (or MEK inhibitor) should be considered for patients with resistant NSCLC harboring MET amplification and/or protein hyperactivation.
• Targeting MET in combination with EGFR inhibition offers a promising strategy to overcome acquired resistance in NSCLC.