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Updated: Nov 4, 2025
Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
When the MET receptor kicks in to resist targeted therapies
Marie Fernandes1, Philippe Jamme1, Alexis B Cortot1,2
1CNRS, Inserm, Institut Pasteur de Lille, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Univ. Lille, Lille, France.
Abstract:
Although targeted therapies have increased the life expectancy of patients with druggable molecular alterations directly involved in tumor development, the efficacy of these therapies is limited by acquired resistances leading to treatment failure. Most targeted therapies, including ones exploiting therapeutic antibodies and kinase inhibitors, are directed against receptor tyrosine kinases (RTKs) or major signaling hubs. Resistances to these therapies arise when inhibition of these targets is bypassed through activation of alternative signaling pathways. In recent years, activation of the receptor tyrosine kinase MET has been shown to promote resistance to various targeted therapies. This casts MET as important actor in resistance. In this review, we describe how the MET receptor triggers resistance to targeted therapies against RTKs such as EGFR, VEGFR, and HER2 and against signaling hubs such as BRAF. We also describe how MET can be its own resistance factor, as illustrated by on-target resistance of lung tumors harboring activating mutations causing MET exon 14 skipping. Interestingly, investigation of all these situations reveals functional physiological relationships between MET and the target of the therapy to which the cancer becomes resistant, suggesting that resistance stems from preexisting mechanisms. Identification of MET as a resistance factor opens the way to co-treatment strategies that are being tested in current clinical trials.
Insights
The receptor tyrosine kinase MET drives resistance to targeted cancer therapies by activating alternative pathways or through on-target mutations. Understanding MET
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted therapies improve outcomes for cancers with specific molecular alterations.
- Acquired resistance limits the long-term efficacy of many targeted therapies.
- Receptor tyrosine kinase MET is increasingly recognized as a key mediator of treatment resistance.
Purpose of the Study:
- To review the mechanisms by which MET activation confers resistance to targeted therapies.
- To explore MET's role in resistance against therapies targeting receptor tyrosine kinases (RTKs) and signaling hubs.
- To discuss the implications of MET's involvement in resistance for future treatment strategies.
Main Methods:
- Literature review of studies investigating MET in acquired resistance.
- Analysis of resistance mechanisms involving MET in cancers treated with RTK inhibitors (e.g., EGFR, VEGFR, HER2) and BRAF inhibitors.
- Examination of MET's role in on-target resistance, including MET exon 14 skipping mutations.
Main Results:
- MET activation bypasses targeted therapies by engaging alternative signaling pathways.
- MET promotes resistance to therapies targeting EGFR, VEGFR, HER2, and BRAF.
- MET can act as a resistance factor through on-target mechanisms like MET exon 14 skipping mutations.
Conclusions:
- MET is a central player in acquired resistance to diverse targeted cancer therapies.
- Preexisting functional relationships between MET and therapeutic targets contribute to resistance.
- Targeting MET offers a promising strategy for overcoming treatment resistance, with co-treatment approaches under clinical investigation.
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