Targeting MET in Non-Small Cell Lung Cancer (NSCLC): A New Old Story?

• Published in: International journal of molecular sciences 2023-06, Vol.24 (12), p.10119
• Main Authors: Spagnolo, Calogera Claudia, Ciappina, Giuliana, Giovannetti, Elisa, Squeri, Andrea, Granata, Barbara, Lazzari, Chiara, Pretelli, Giulia, Pasello, Giulia, Santarpia, Mariacarmela
• Format: Article
• Language: English
• Subjects: Antitumor activity; Binding sites; Biomarkers; c-Met protein; Cancer therapies; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell growth; Clinical medicine; Clinical trials; Combinatorial analysis; Deregulation; Epidermal growth factor; Gene amplification; Humans; Immunotherapy; Kinases; Ligands; Lung cancer; Lung cancer, Non-small cell; Lung cancer, Small cell; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Lymphoma; Medical research; Medicine, Experimental; mesenchymal-epithelial transition (MET); Metastases; Monoclonal antibodies; Motility; Mutation; non-small cell lung cancer (NSCLC); Non-small cell lung carcinoma; oncogene; Pharmacology; predictive biomarkers; Protein Kinase Inhibitors - pharmacology; Protein-tyrosine kinase; Proteins; Proto-Oncogene Proteins c-met - metabolism; Review; Sarcoma; Stem cells; Subgroups; targeted therapy; Transcription factors; Tyrosine; tyrosine kinase inhibitors (TKIs)
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms241210119

In recent years, we have seen the development and approval for clinical use of an increasing number of therapeutic agents against actionable oncogenic drivers in metastatic non-small cell lung cancer (NSCLC). Among them, selective inhibitors, including tyrosine kinase inhibitors (TKIs) and monoclonal antibodies targeting the mesenchymal-epithelial transition (MET) receptor, have been studied in patients with advanced NSCLC with deregulation, primarily due to exon 14 skipping mutations or amplification. Some MET TKIs, including capmatinib and tepotinib, have proven to be highly effective in this molecularly defined subgroup of patients and are already approved for clinical use. Other similar agents are being tested in early-stage clinical trials with promising antitumor activity. The purpose of this review is to provide an overview of MET signaling pathways, oncogenic alterations primarily focusing on exon 14 skipping mutations, and the laboratory techniques used to detect alterations. Furthermore, we will summarize the currently available clinical data and ongoing studies on MET inhibitors, as well as the mechanisms of resistance to MET TKIs and new potential strategies, including combinatorial approaches, to improve the clinical outcomes of exon 14-altered NSCLC patients.