The mesenchymal-epithelial transition factor (MET) exon 14 skipping mutation is mainly caused by the loss of c-Cbl tyrosine binding site. This mutation could result in a decrease in the degradation rate of proteasome-mediated MET proteins, trigger continuous activation of downstream pathways, and ultimately lead to tumorigenesis. The incidence of MET exon 14 skipping mutation in patients with non-small cell lung cancer (NSCLC) is 0.9% to 4.0%. Patients with advanced NSCLC are recommended to test MET exon 14 skipping mutations who may benefit from MET inhibitors-targeted therapy. MET inhibitors have a high objective response rate and good safety profiles, which could prolong the survival of NSCLC patients with MET exon 14 skipping mutations. The Lung Cancer Specialty Committee of Chinese Elderly Health Care Association organized multidisciplinary experts to give suggestions on the important issues of clinical aspects for targeted therapy of MET exon 14 skipping mutation in NSCLC according to the clinical practice experiences and evidences based medicine. "Expert Consensus on Targeted Therapy of NSCLC with MET Exon 14 Skipping Mutation" is proposed, aiming to provide standardized guidances for the clinical practice of Chinese physicians.
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Humans ; Aged ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/genetics* ; Consensus ; Proto-Oncogene Proteins c-met/genetics* ; Mutation ; Exons ; Protein Kinase Inhibitors/therapeutic use*

MET gene is a proto-oncogene, which encodes MET protein with tyrosine kinase activity. After binding to its ligand, hepatocyte growth factor, MET protein can induce MET dimerization and activate downstream signaling pathways, which plays a crucial role in tumor formation and metastasis. Savolitinib, as a specific tyrosine kinase inhibitor (TKI) targeting MET, selectively inhibits the phosphorylation of MET kinase with a significant inhibitory effect on tumors with MET abnormalities. Based on its significant efficacy shown in the registration studies, savolitinib was approved for marketing in China on June 22, 2021 for the treatment of advanced non-small cell lung cancer with MET 14 exon skipping mutations. In addition, many studies have shown that MET TKIs are equally effective in patients with advanced solid tumors with MET gene amplification or MET protein overexpression, and relevant registration clinical studies are ongoing. The most common adverse reactions during treatment with savolitinib include nausea, vomiting, peripheral edema, pyrexia, and hepatotoxicity. Based on two rounds of extensive nationwide investigations to guide clinicians, the consensus is compiled to use savolitinib rationally, prevent and treat various adverse reactions scientifically, and improve the clinical benefits and quality of life of patients. This consensus was prepared under the guidance of multidisciplinary experts, especially including the whole-process participation and valuable suggestions of experts in Traditional Chinese Medicine, thus reflecting the clinical treatment concept of integrated Chinese and western medicines.
Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; Lung Neoplasms/pathology* ; Consensus ; Quality of Life ; Proto-Oncogene Proteins c-met/genetics* ; Protein Kinase Inhibitors/adverse effects* ; Drug-Related Side Effects and Adverse Reactions ; Mutation

Humans ; Carcinoma, Non-Small-Cell Lung/genetics* ; China ; Consensus ; East Asian People ; Immunohistochemistry ; Lung Neoplasms/genetics* ; Proto-Oncogene Proteins c-met/genetics*

Mesenchymal-epithelial transition factor (MET) amplification is an important driver of resistance in epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC), and the combination of MET proto-oncogene (MET) and EGFR-tyrosine kinase inhibitors (TKIs) has shown promise in overcoming this molecularly defined acquired resistance. Emerging data also demonstrate MET amplification as a resistance driver to TKIs-treated anaplastic lymphoma kinase (ALK)-, RET-, and ROS1-fusion NSCLC. Here, we review the literature on recent research progress of MET amplification as a resistance driver to targeted therapy in oncogene-driven NSCLC and summarize the progress of clinical strategies to overcome the resistance mechanism.
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Carcinoma, Non-Small-Cell Lung/genetics* ; Drug Resistance, Neoplasm/genetics* ; ErbB Receptors/genetics* ; Humans ; Lung Neoplasms/pathology* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins/genetics* ; Proto-Oncogene Proteins c-met/genetics*

Targeted therapy is an important therapeutic method for advanced non-small cell lung cancer with driver gene alteration.However,resistance to targeted therapy will inevitably happen in clinical practice,which has become a major issue demanding prompt solution.Studies have demonstrated that bypass resistance mediated by the activation of hepatocyte growth factor(HGF)/mesenchymal-epithelial transition factor(MET)signaling pathway is a common cause of resistance to targeted therapy.Presently,relevant studies have accumulated rich experience in the specific mechanisms.To be brief,HGF/MET is an important target for overcoming the resistance to targeted therapy and promises to be a leading biomarker for judging and observing the occurrence of resistance.This paper introduces the recent studies concerning the effects and mechanisms of HGF/MET signaling pathway on resistance to targeted therapy.
Carcinoma, Non-Small-Cell Lung/genetics* ; Epithelial-Mesenchymal Transition ; Hepatocyte Growth Factor ; Humans ; Lung Neoplasms/genetics* ; Proto-Oncogene Proteins c-met/metabolism* ; Signal Transduction

Acrylamides ; Aniline Compounds ; Carcinoma, Non-Small-Cell Lung/genetics* ; Crizotinib/therapeutic use* ; Drug Resistance, Neoplasm/genetics* ; Erlotinib Hydrochloride/therapeutic use* ; Humans ; Lung Neoplasms/genetics* ; Mutation ; Protein Kinase Inhibitors/therapeutic use* ; Proto-Oncogene Proteins c-met/genetics*

Recently, targeted therapy has achieved great success in the treatment of non-small cell lung cancer (NSCLC) patients. Mesenchymal to epithelial transition factor (MET) is considered to be another important molecular target for NSCLC since epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). Accumulating clinical trials and case reports have confirmed that MET inhibitors exhibited a potential prospect in treating patients with MET 14 exon skipping alterations, suggesting that MET 14 exon skipping mutation might be an effective biomarker for MET inhibitors, which remains to be confirmed by more clinical data. This review summarizes current research about the molecular mechanism, clinicopathological characterization, treatment strategies and drug resistance mechanisms of MET 14 exon skipping alterations in NSCLC.
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Carcinoma, Non-Small-Cell Lung ; drug therapy ; genetics ; Exons ; genetics ; Humans ; Lung Neoplasms ; drug therapy ; genetics ; Molecular Targeted Therapy ; Mutation ; Proto-Oncogene Proteins c-met ; genetics

Recepteur d'origine nantais (RON) is a receptor tyrosine kinase belonging to the subfamily of which c-MET is the prototype. Large epidemiologic studies have confirmed the strong association between RON and gastric cancer development. Constitutive activation of RON signaling directly correlates with tumorigenic phenotypes of gastric cancer and a poor survival rate in advanced gastric cancer patients. In this review, we focus on recent evidence of the aberrant expression and activation of RON in gastric cancer tumors and provide insights into the mechanism of RON signaling associated with gastric cancer progression and metastasis. Current therapeutics against RON in gastric cancer are summarized.
Epidemiologic Studies ; Humans ; Neoplasm Metastasis ; Phenotype ; Protein-Tyrosine Kinases ; Proto-Oncogene Proteins c-met ; Stomach Neoplasms ; Survival Rate

Objective To investigate the expressions of CD44,CD47,and c-met in ovarian clear cell carcinoma (OCCC) tissue and their correlations with clinical variables and prognosis. Methods Immunohistochemical method was used to investigate the expressions of CD44,CD47,and c-met in tissues from 86 OCCC patients and the relationships of their expressions with the clinicopathological factors of OCCC were analyzed. Results The expressions of CD44,CD47,and c-met were significantly high in OCCC tissues (90.7%,91.9%,and 94.2%,respectively). The strong positive expressions of CD44 and CD47 were significantly correlated with advanced International Federation of Gynecology and Obstetrics stages,chemotherapeutic resistance,and poor prognosis (all P<0.05),the strong positive expression of c-met was significantly correlated with chemotherapeutic resistance and poor prognosis (all P<0.05),whereas there was no correlation between the strong positive expressions of CD44,CD47,and c-met and the lymphatic node metastasis. COX survival analysis revealed that advanced International Federation of Gynecology and Obstetrics stages and high expressions of CD44,CD47 and c-met were independent risk factors for poor prognosis (P<0.05). There was a positive correlation between CD44 (or CD47) and c-met and between CD44 and CD47 (the Spearman correlation coefficient rwas 0.783,0.776,and 0.835,respectively,all P<0.01). Conclusions The expressions of CD44,CD47,and c-met increase in OCCC tissues and are correlated with each other. High expressions of CD44,CD47,and c-met are independent factors for poor prognosis.
Adenocarcinoma, Clear Cell ; metabolism ; CD47 Antigen ; metabolism ; Female ; Humans ; Hyaluronan Receptors ; metabolism ; Lymphatic Metastasis ; Ovarian Neoplasms ; metabolism ; Prognosis ; Proto-Oncogene Proteins c-met ; metabolism ; Survival Analysis

OBJECTIVETo explore the correlation of c-met protein with the clinical staging and cell differentiation of esophageal squamous cell carcinoma (ESCC).

METHODSA total of 100 patients with ESCC were enrolled were examined for expression of c-met protein using immunohistochemistry, and the patients in negative and positive c-met expression groups were compared for clinicopathological characteristics and overall survival.

RESULTSs The 100 ESCC patients included 67 male and 33 female patients with a median age of 59 years; 49 of the patients were negative and 51 were positive for c-met expression. Positive c-met expression was significantly correlated with advanced TMN stages and lower tumor differentiation. Kaplan-Meier survival curve showed that the median survival time of c-met-positive patients was significantly reduced compared with that of c-met-negative patients (30.9 vs 48.2 months, P<0.05). COX regression analysis showed that c-met was a independent risk factor for the overall survival of the patients (HR: 2.34, 95% CI: 1.63-4.54, P<0.05).

CONCLUSIONA positive expression of c-met protein is significantly correlated with an advanced TMN stage, lower tumor differentiation and a poor prognosis, and may serve as a indicator for predicting the prognosis of ESCC.

Carcinoma, Squamous Cell ; diagnosis ; metabolism ; Esophageal Neoplasms ; diagnosis ; metabolism ; Female ; Humans ; Immunohistochemistry ; Kaplan-Meier Estimate ; Male ; Middle Aged ; Neoplasm Staging ; Prognosis ; Proportional Hazards Models ; Proto-Oncogene Proteins c-met ; metabolism ; Risk Factors