# Targeting Mesenchymal-Epidermal Transition (MET) Aberrations in Non-Small Cell Lung Cancer: Current Challenges and Therapeutic Advances

## TL;DR

This paper reviews how abnormal MET activation contributes to non-small cell lung cancer and discusses new treatment strategies to target this pathway.

## Contribution

The paper provides a comprehensive overview of MET's role in NSCLC and highlights emerging therapeutic strategies to target MET alterations.

## Key findings

- Aberrant MET activation is associated with poor clinical outcomes in NSCLC.
- MET-targeted therapies like capmatinib and tepotinib show promise in treating MET exon 14 skipping mutations.
- Combination therapies with MET inhibitors and EGFR inhibitors may overcome drug resistance in NSCLC.

## Abstract

Non-small cell lung cancer (NSCLC) represents the most prevalent form of lung cancer. Abnormal activation of mesenchymal transition (MET) proto-oncogenes serves as a key oncogenic driver in NSCLC and is correlated with poor clinical outcomes. The activation of the MET pathway is not only a carcinogenic factor for NSCLC but also a highly potential therapeutic target. Such abnormal MET activation may occur through MET gene mutations, MET gene amplification or transcriptional upregulation without amplification. Although MET tyrosine kinase inhibitors (TKIs) are currently the most widely employed class of MET-targeted agents, their clinical benefits remain limited and insufficient to fully meet clinical needs. In recent years, monoclonal antibodies directed against specific MET epitopes have demonstrated encouraging clinical efficacy in various trials. Furthermore, combination therapeutic strategies—especially with EGFR inhibitors—have demonstrated greater clinical potential compared to monotherapy by overcoming drug resistance and enhancing efficacy. Ongoing research in this field is essential to fully integrate MET-targeted therapies into routine clinical practice and expand treatment options for patients with NSCLC. This review comprehensively summarizes the structure and physiological functions of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its role in acquired resistance to targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC.

The mesenchymal–epithelial transition (MET) receptor is a tyrosine kinase activated by its sole known ligand, hepatocyte growth factor (HGF). MET signaling regulates key cellular processes, including proliferation, survival, migration, motility, and angiogenesis. Dysregulation and hyperactivation of this pathway are implicated in multiple malignancies, including lung, breast, colorectal, and gastrointestinal cancers. In non–small cell lung cancer (NSCLC), aberrant activation of the MET proto-oncogene contributes to 1% of known oncogenic drivers and is associated with poor clinical outcomes. Several mechanisms can induce MET hyperactivation, including MET gene amplification, transcriptional upregulation of MET or HGF, MET fusion genes, and MET exon 14 skipping mutations. Furthermore, MET pathway activation represents a frequent mechanism of acquired resistance to EGFR- and ALK-targeted tyrosine kinase inhibitors (TKIs) in EGFR- and ALK-driven NSCLCs. Although MET has long been recognized as a promising therapeutic target in NSCLC, the clinical efficacy of MET-targeted therapies has historically lagged behind that of EGFR and ALK inhibitors. Encouragingly, several MET TKIs such as capmatinib, tepotinib, and savolitinib have been approved for the treatment of MET exon 14 skipping mutations. They have also demonstrated potential in overcoming MET-driven resistance to EGFR TKIs or ALK TKIs. On 14 May 2025, the U.S. Food and Drug Administration granted accelerated approval to telisotuzumab vedotin-tllv for adult patients with locally advanced or metastatic non-squamous NSCLC whose tumors exhibit high c-Met protein overexpression and who have already received prior systemic therapy. In this review, we summarize the structure and physiological role of the MET receptor, the molecular mechanisms underlying aberrant MET activation, its contribution to acquired resistance against targeted therapies, and emerging strategies for effectively targeting MET alterations in NSCLC.