• Biomarkers
• Diagnosis
• Gastric cancer
• Predicting treatment response
• Prognosis

• Stomach Neoplasms/diagnosis
• Humans
• Biomarkers, Tumor/urine
• Prognosis

• Gastric cancer
• Hepatocyte growth factor
• Prognosis assessment
• Review
• Targeted therapy
• c-Met

• Ferroptosis
• Gastric cancer
• Lipid metabolism
• Lipid peroxidation
• Systematic review

• cell line
• gastric cancer
• proto-oncogene protein c-met
• tumor
• tyrosine kinase inhibitors

• Humans
• Proto-Oncogene Proteins c-met/metabolism
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• Stomach Neoplasms/metabolism
• Stomach Neoplasms/genetics
• Cell Line, Tumor
• Animals
• Triazines/pharmacology
• Mice
• Xenograft Model Antitumor Assays
• Benzamides/pharmacology
• Cell Proliferation/drug effects
• Esophageal Neoplasms/drug therapy
• Esophageal Neoplasms/pathology
• Esophageal Neoplasms/metabolism
• Signal Transduction/drug effects
• Mice, Nude
• Protein Kinase Inhibitors/pharmacology
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Molecular Targeted Therapy
• Female
• Imidazoles

• 03-2020-3 Boramae Medical Center

• Gastric cancer
• MET alterations
• MET testing
• MET tyrosine kinase inhibitors
• savolitinib

• Humans
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Proto-Oncogene Proteins c-met/metabolism
• Proto-Oncogene Proteins c-met/genetics
• Protein Kinase Inhibitors/therapeutic use
• Protein Kinase Inhibitors/pharmacology
• Molecular Targeted Therapy
• Drug Resistance, Neoplasm
• Signal Transduction/drug effects
• Antineoplastic Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Tyrosine Kinase Inhibitors

• 81602057 National Natural Science Foundation of China
• Z210015 Beijing Natural Science Foundation

• Humans
• Stomach Neoplasms/pathology
• Exosomes
• Ascites/pathology
• Cell Line, Tumor
• MicroRNAs

• Ministry of Science and ICT, South Korea

• angiogenesis
• cancer
• cannabinoid-like molecules
• endocannabinoidome
• endocannabinoids

At present, a large number of studies have demonstrated that c-Met generally exerts a crucial function of promoting tumor cells proliferation and differentiation in digestive system tumors. c-Met also mediates tumor progression and drug resistance by signaling interactions with other oncogenic molecules and then activating downstream pathways. Therefore, c-Met is a promising target for the treatment of digestive system tumors. Many anti-tumor therapies targeting c-Met (tyrosine kinase inhibitors, monoclonal antibodies, and adoptive immunotherapy) have been developed in treating digestive system tumors. Some drugs have been successfully applied to clinic, but most of them are defective due to their efficacy and complications. In order to promote the clinical application of targeting c-Met drugs in digestive system tumors, it is necessary to further explore the mechanism of c-Met action in digestive system tumors and optimize the anti-tumor treatment of targeting c-Met drugs. Through reading a large number of literatures, the author systematically reviewed the biological functions and molecular mechanisms of c-Met associated with tumor and summarized the current status of targeting c-Met in the treatment of digestive system tumors so as to provide new ideas for the treatment of digestive system tumors.

• MET receptor tyrosine kinase
• antibody-drug conjugate
• drug delivery
• duocarmycin
• in vitro cytotoxicity
• mouse monoclonal antibody
• therapeutic efficacy
• tumor xenograft model

Gastric cancer (GC) is one of the most common and deadliest types of cancer worldwide due to its delayed diagnosis and high metastatic frequency, but its exact pathogenesis has not been fully elucidated. ETS homologous factor (EHF) is an important member of the ETS family and contributes to the pathogenesis of multiple malignant tumors. To date, whether EHF participates in the development of GC via the c-Met signaling pathway remains unclear.

To investigate the role and mechanism of EHF in the occurrence and development of GC.

The expression of EHF mRNA in GC tissues and cell lines was measured by quantitative PCR. Western blotting was performed to determine the protein expression of EHF, c-Met, and its downstream signal molecules. The EHF expression in GC tissues was further detected by immunohistochemical staining. To investigate the role of EHF in GC oncogenesis, small interfering RNA (siRNA) against EHF was transfected into GC cells. The cell proliferation of GC cells was determined by Cell Counting Kit-8 and colony formation assays. Flow cytometry was performed following Annexin V/propidium iodide (PI) to identify apoptotic cells and PI staining to analyze the cell cycle. Cell migration and invasion were assessed by transwell assays.

The data showed that EHF was upregulated in GC tissues and cell lines in which increased expression of c-Met was also observed. Silencing of EHF by siRNA reduced the proliferation of GC cells. Inhibition of EHF induced significant apoptosis and cell cycle arrest in GC cells. Cell migration and invasion were significantly inhibited. EHF silencing led to c-Met downregulation and further blocked the Ras/c-Raf/extracellular signal-related kinase 1/2 (Erk1/2) pathway. Additionally, phosphatase and tensin homolog was upregulated and glycogen synthase kinase 3 beta was deactivated. Moreover, inactivation of signal transducer and activator of transcription 3 was detected following EHF inhibition, leading to inhibition of the epithelial-to-mesenchymal transition (EMT).

These results suggest that EHF plays a key role in cell proliferation, invasion, apoptosis, the cell cycle and EMT via the c-Met pathway. Therefore, EHF may serve as an antineoplastic target for the diagnosis and treatment of GC.

• Gastric cancer
• ETS homologous factor
• c-Met
• Antineoplastic target
• Signaling pathway

• Cell Line, Tumor
• Cell Movement
• Cell Proliferation
• Epithelial-Mesenchymal Transition
• Gene Expression Regulation, Neoplastic
• Humans
• Neoplasm Invasiveness
• Stomach Neoplasms/genetics

Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.

• HGF
• MET amplification
• MET over-expression
• gastric cancer
• monoclonal antibodies
• tyrosine kinase inhibitors

• BRCA1
• BRCA2
• PARP inhibitor
• c-Met inhibitor
• gastric cancer

• Animals
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Apoptosis/drug effects
• Cell Line, Tumor
• Clone Cells
• DNA Damage
• Histones/metabolism
• Humans
• Indoles/pharmacology
• Indoles/therapeutic use
• Mice
• Models, Biological
• Neoplasm Proteins/metabolism
• Piperazines/pharmacology
• Piperazines/therapeutic use
• Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Quinazolines/pharmacology
• Quinazolines/therapeutic use
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/pathology
• Sulfonamides/pharmacology
• Sulfonamides/therapeutic use
• Xenograft Model Antitumor Assays

• Biomedical Research Foundation

• C-Met
• Cancer immunotherapy
• Chimeric antigen receptor
• PD-1
• Tumor microenvironment

The receptor tyrosine kinase c-MET regulates processes essential for tissue remodeling and mammalian development. The dysregulation of c-MET signaling plays a role in tumorigenesis. The aberrant activation of c-MET, such as that caused by gene amplification or mutations, is associated with many cancers. c-MET is therefore an attractive therapeutic target, and inhibitors are being tested in clinical trials. However, inappropriate patient selection criteria, such as low amplification or expression level cut-off values, have led to the failure of clinical trials. To include patients who respond to MET inhibitors, the selection criteria must include MET oncogenic addiction. Here, the efficacy of ABN401, a MET inhibitor, was investigated using histopathologic and genetic analyses in MET-addicted cancer cell lines and xenograft models. ABN401 was highly selective for 571 kinases, and it inhibited c-MET activity and its downstream signaling pathway. We performed pharmacokinetic profiling of ABN401 and defined the dose and treatment duration of ABN401 required to inhibit c-MET phosphorylation in xenograft models. The results show that the efficacy of ABN401 is associated with MET status and they highlight the importance of determining the cut-off values. The results suggest that clinical trials need to establish the characteristics of each sample and their correlations with the efficacy of MET inhibitors.

• c-MET
• c-MET inhibitor (ABN401)
• diagnostic biomarker
• gastric cancer
• non-small cell lung cancer (NSCLC)
• patient-derived xenograft (PDX) models
• pharmacodynamics
• pharmacokinetics

Targeted cancer therapies are powerful alternatives to chemotherapies or can be used complementary to these. Yet, the response to targeted treatments depends on a variety of factors, including mutations and expression levels, and therefore their outcome is difficult to predict. Here, we develop a mechanistic model of gastric cancer to study response and resistance factors for cetuximab treatment. The model captures the EGFR, ERK and AKT signaling pathways in two gastric cancer cell lines with different mutation patterns. We train the model using a comprehensive selection of time and dose response measurements, and provide an assessment of parameter and prediction uncertainties. We demonstrate that the proposed model facilitates the identification of causal differences between the cell lines. Furthermore, our study shows that the model provides predictions for the responses to different perturbations, such as knockdown and knockout experiments. Among other results, the model predicted the effect of MET mutations on cetuximab sensitivity. These predictive capabilities render the model a basis for the assessment of gastric cancer signaling and possibly for the development and discovery of predictive biomarkers.

Unraveling the causal differences between drug responders and non-responders is an important challenge. The information can help to understand molecular mechanisms and to guide the selection and design of targeted therapies. Here, we approach this problem for cetuximab treatment for gastric cancer using mechanistic mathematical modeling. The proposed model describes responder and non-responder gastric cancer cell lines and can predict the response in several validation experiments. Our analysis provides a differentiated view on mutations and explains, for instance, the relevance of MET mutations and the insignificance of PIK3CA mutation in the considered cell lines. The model might potentially provide the basis for understanding the recent failure of several clinical studies.

• Antibodies, Monoclonal/genetics
• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents/pharmacology
• Biomarkers, Tumor/metabolism
• Cell Line, Tumor/drug effects
• Cell Proliferation/drug effects
• Cetuximab/genetics
• Cetuximab/metabolism
• Cetuximab/pharmacology
• Drug Resistance, Neoplasm/drug effects
• ErbB Receptors/metabolism
• Humans
• Models, Biological
• Models, Statistical
• Phosphatidylinositol 3-Kinases/metabolism
• Proto-Oncogene Proteins/metabolism
• R Factors
• Signal Transduction/physiology
• Stomach Neoplasms/drug therapy
• Stomach Neoplasms/genetics
• ras Proteins/metabolism

• 4-phenoxypyridines
• Synthesis
• antitumor mechanism
• c-met inhibitors
• cytotoxic activities
• semicarbazone moieties.

• cancer-associated fibroblasts
• exosome
• metastasis
• pre-metastatic niche
• tumor microenvironment

• Epithelial-Mesenchymal Transition
• Exosomes/genetics
• Exosomes/metabolism
• Exosomes/pathology
• Humans
• Neoplasm Metastasis/genetics
• Neoplasm Metastasis/pathology
• Stem Cell Niche
• Tumor Microenvironment

• lung cancer
• drug resistance
• amplification
• met exon 14
• kras

• Animals
• Antineoplastic Agents/pharmacology
• Carcinoma, Non-Small-Cell Lung/diagnosis
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Carcinoma, Non-Small-Cell Lung/genetics
• Cell Line, Tumor
• Crizotinib/pharmacology
• DNA Copy Number Variations
• Disease Models, Animal
• Drug Resistance, Neoplasm/genetics
• Exons
• Gene Amplification
• Gene Expression Regulation, Neoplastic
• Humans
• In Situ Hybridization, Fluorescence
• Lung Neoplasms/diagnosis
• Lung Neoplasms/drug therapy
• Lung Neoplasms/genetics
• Mice
• Models, Biological
• Mutation
• Phosphatidylinositol 3-Kinases/genetics
• Positron Emission Tomography Computed Tomography
• Protein Kinase Inhibitors/pharmacology
• Proto-Oncogene Proteins c-met/genetics
• Proto-Oncogene Proteins p21(ras)/genetics
• Signal Transduction/drug effects
• Xenograft Model Antitumor Assays

• R01 CA135257 NCI NIH HHS
• R01 CA222823 NCI NIH HHS
• R35 CA220497 NCI NIH HHS

• CoMFA
• CoMSIA
• MMGBSA
• c-Met kinase
• design
• entropy calculations
• free energy calculation
• molecular dynamics simulation

The extracellular matrix (ECM) is a crucial component of the tumor microenvironment involved in numerous cellular processes that contribute to cancer progression. It is acknowledged that tumor–stromal cell communication is driven by a complex and dynamic network of cytokines, growth factors and proteases. Thus, the ECM works as a reservoir for bioactive molecules that modulate tumor cell behavior. The hepatocyte growth factor (HGF) produced by tumor and stromal cells acts as a multifunctional cytokine and activates the c-MET receptor, which is expressed in different tumor cell types. The HGF/c-MET signaling pathway is associated with several cellular processes, such as proliferation, survival, motility, angiogenesis, invasion and metastasis. Moreover, c-MET activation can be promoted by several ECM components, including proteoglycans and glycoproteins that act as bridging molecules and/or signal co-receptors. In contrast, c-MET activation can be inhibited by proteoglycans, matricellular proteins and/or proteases that bind and sequester HGF away from the cell surface. Therefore, understanding the effects of ECM components on HGF and c-MET may provide opportunities for novel therapeutic strategies. Here, we give a short overview of how certain ECM components regulate the distribution and activation of HGF and c-MET.

• HGF
• c-MET
• cancer progression
• extracellular matrix
• tumor microenvironment

• Animals
• Extracellular Matrix/metabolism
• Hepatocyte Growth Factor/metabolism
• Humans
• Neoplasms/metabolism
• Neoplasms/pathology
• Proto-Oncogene Proteins c-met/metabolism
• Signal Transduction

The HGF/c-MET pathway is active in the development of digestive system cancers, indicating that inhibition of HGF/c-MET signaling may have therapeutic potential. Various HGF/c-MET signaling inhibitors, mainly c-MET inhibitors, have been tested in clinical trials. The observed efficacy and adverse events of some c-MET inhibitors were not very suitable for treating digestive system cancers. The development of new HGF/c-MET inhibitors in preclinical studies may bring promising treatments and synergistic combination (traditional anticancer drugs and c-MET inhibitors) strategies provided anacceptable safety and tolerability. Insights into miRNA biology and miRNA therapeutics have made miRNAs attractive tools to inhibit HGF/c-MET signaling. Recent reports show that several microRNAs participate in inhibiting HGF/c-MET signaling networks through antagonizing c-MET or HGF in digestive system cancers, and the miRNAs-HGF/c-MET axis plays crucial and novel roles for cancer treatment. In the current review, we will discuss recent findings about inhibitors of HGF/c-MET signaling in treating digestive system cancers, and how miRNAs regulate digestive system cancers via mediating HGF/c-MET pathway.

• HGF
• c-MET
• digestive system cancers
• miRNA

• c-Met inhibitors
• c-Met/HGF pathway
• resistance to targeted agents
• upper gastrointestinal cancers

• Animals
• Antineoplastic Agents/therapeutic use
• Digestive System Neoplasms/drug therapy
• Digestive System Neoplasms/enzymology
• Digestive System Neoplasms/pathology
• Drug Resistance, Neoplasm
• Hepatocyte Growth Factor/metabolism
• Humans
• Molecular Targeted Therapy
• Protein Kinase Inhibitors/therapeutic use
• Proto-Oncogene Proteins c-met/antagonists & inhibitors
• Proto-Oncogene Proteins c-met/metabolism
• Signal Transduction/drug effects