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Targeting c-MET in the battle against advanced nonsmall-cell lung cancer
Lorenza Landi1, Gabriele Minuti, Armida D'Incecco
1Istituto Toscano Tumori, Ospedale Civile, Livorno, Italy.
Purpose Of Review:
The mesenchymal-epidermal transition (c-MET) receptor tyrosine kinase has a central role in the cancer cell's survival. MET and its ligand, hepatocyte growth factor (HGF), have recently been identified as promising targets in solid tumors, including nonsmall-cell lung cancer (NSCLC).
Recent Findings:
Aberrant MET activation can be the result of different mechanisms such as MET and HGF overexpression, MET gene amplification or mutation. Retrospective studies in NSCLC showed that MET gene copy number is a negative prognostic factor, although few data are available on the role of MET mutations. In preclinical models, cell lines with MET gene amplification are extremely sensitive to MET inhibition. Although the inner presence of gene amplification is a rare event (1-7% cases), MET amplification has emerged as one of the critical events for acquired resistance in epidermal growth factor receptor (EGFR) mutated lung adenocarcinomas refractory to EGFR-tyrosine kinase inhibitors (TKIs). In NSCLC with acquired resistance to EGFR-TKIs, MET amplification occurs in up to 20% cases and preclinical and clinical data indicated MET and EGFR co-inhibition as a potential effective strategy to overcome resistance.
Summary:
MET has recently emerged as a promising target, and ongoing trials will clarify the role of anti-MET strategies in NSCLC.
Insights
The mesenchymal-epidermal transition (c-MET) receptor tyrosine kinase is crucial for cancer cell survival. Targeting MET and hepatocyte growth factor (HGF) shows promise for treating solid tumors like nonsmall-cell lung cancer (NSCLC).
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The mesenchymal-epidermal transition (c-MET) receptor tyrosine kinase plays a key role in cancer cell survival.
- MET and its ligand, hepatocyte growth factor (HGF), are emerging as significant therapeutic targets in solid tumors, particularly nonsmall-cell lung cancer (NSCLC).
Purpose of the Study:
- To review the role of MET and HGF as therapeutic targets in solid tumors.
- To explore the mechanisms of aberrant MET activation and its implications in NSCLC.
- To discuss the potential of MET-targeted therapies in overcoming resistance to existing treatments.
Main Methods:
- Review of preclinical and clinical data on MET activation, amplification, and mutation in NSCLC.
- Analysis of retrospective studies on MET gene copy number and its prognostic value.
- Evaluation of the efficacy of MET inhibitors and combination therapies.
Main Results:
- Aberrant MET activation occurs through various mechanisms, including overexpression, amplification, or mutation.
- MET gene copy number is a negative prognostic factor in NSCLC.
- MET amplification is a critical mechanism of acquired resistance to EGFR-tyrosine kinase inhibitors (TKIs) in lung adenocarcinomas, occurring in up to 20% of cases.
- Preclinical and clinical data suggest that MET and EGFR co-inhibition is a viable strategy to overcome resistance.
Conclusions:
- MET is a promising therapeutic target in NSCLC.
- Ongoing clinical trials are investigating the efficacy of anti-MET strategies.
- Targeting MET, particularly in combination with EGFR inhibition, holds potential for managing resistant NSCLC.
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