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Published on: May 7, 2020
Non-small-cell lung cancer: how to manage MET exon 14 skipping mutant disease
Juan Bautista Blaquier1, Gonzalo Recondo1
1Thoracic Oncology Unit, Medical Oncology, Center for Medical Education and Clinical Research (CEMIC), Buenos Aires, Argentina.
Abstract:
Several oncogenic mechanisms have been identified for MET, including MET amplification, fusions, mutations in the tyrosine kinase domain and exon 14 skipping alterations. MET exon 14 mutations are found in about 3-5% of non-small-cell lung cancers. Dysregulation of the MET receptor leads to cell proliferation and survival by activation of the PI3K-AKT-TOR and RAS-RAF-MET-ERK canonical pathways. Targeting the MET tyrosine kinase domain in the setting of MET exon 14 mutations using effective MET tyrosine kinase inhibitors is a current targeted therapy option for patients with metastatic lung cancer. In this Review, we focus on the management of patients with MET exon 14 skipping alterations by addressing the biology of the MET receptor and exon 14 skipping mutations, current treatment strategies, and sequential treatment options based on resistance mechanisms to MET inhibitors in patients with non-small-cell lung cancer.
Insights
MET exon 14 skipping alterations drive non-small-cell lung cancer. MET tyrosine kinase inhibitors offer targeted therapy, with this review detailing management strategies and resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- MET receptor dysregulation, through amplification, fusion, mutation, or exon 14 skipping, drives oncogenesis.
- MET exon 14 skipping alterations occur in 3-5% of non-small-cell lung cancers (NSCLC).
- MET pathway activation (PI3K-AKT-TOR, RAS-RAF-MET-ERK) promotes cancer cell proliferation and survival.
Purpose of the Study:
- To review the biology of MET exon 14 skipping mutations in NSCLC.
- To discuss current targeted therapy strategies using MET tyrosine kinase inhibitors.
- To explore sequential treatment options considering resistance mechanisms.
Main Methods:
- Literature review of studies on MET exon 14 skipping alterations in NSCLC.
- Analysis of oncogenic mechanisms and targeted therapy approaches.
- Examination of resistance patterns to MET inhibitors.
Main Results:
- MET exon 14 skipping is a validated oncogenic driver in NSCLC.
- MET tyrosine kinase inhibitors are effective in patients with these alterations.
- Understanding resistance mechanisms is crucial for optimizing treatment sequencing.
Conclusions:
- Targeted inhibition of MET is a key therapeutic strategy for NSCLC with MET exon 14 skipping.
- Further research into resistance mechanisms will inform future treatment paradigms.
- Personalized management strategies are essential for improving patient outcomes.
