Modulation of the c-Met/hepatocyte growth factor pathway in small cell lung cancer

Activation of the c-Met pathway targets the PI3K pathway in small cell lung cancer

HGF stimulation of c-Met-overexpressing H69 small cell lung cancer cells (40 ng/ml, 15 min) resulted in an increase of reactive oxygen species

Met is necessary for lung cancer cell lines growth and survival.

In lung adenocarcinoma, c-Met activation may take place either ligand-dependently or ligand-independently via c-Met. overexpression.

findings show that amplification of MET causes gefitinib resistance in lung cancer by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors

MET amplification occurs independently of EGFR(T790M) mutations in lung adenocarcinoma

MET amplification associated with EGFR amplification is associated with non-small cell lung cancer

MET increased gene copy number and primary resistance to gefitnib therapy in non-small-cell lung cancer patients are reported.

a critical role of Met gene dose in non-small cell lung cancer , suggesting that Met may be a specific molecular therapeutic target in selected non-small cell lung cancer patients with increased Met copy number.

Activation of MET by gene amplification or by splice mutations deleting the juxtamembrane domain is associated with primary resected lung cancers.

study determined PAX5 could regulate transcription of c-Met; the phospho-c-Met (active form) & PAX5 were both localized to the same intra-nuclear compartment in hepatocyte growth factor treated small-cell lung cancer cells and interacted with each other

MET increased gene copy number is an independent negative prognostic factor in surgically resected non-small-cell lung cancer

EGFR T790M mutation and c-MET amplification can occur in tyrosine kinase inhibitor-resistant non-small cell lung cancer with wild-type EGFR. These genetic defects might be related to different survival outcome.

The MET in lung cancer tissues contained nonsynonymous mutations in the semaphorin and juxtamembrane domains but not in the tyrosine kinase domain. East Asians, African-Americans, and Caucasians had different MET genotypes and haplotypes.

Using lung adenocarcinoma samples and cell lines derived from lung adenocarcinomas, we demonstrated that the gene copy number for MET in lung adenocarcinoma tissue samples was increased over EGFR, HGF, and PXN and that it correlated with better prognosis

High MET gene copy number is associated with non-small cell lung cancer.

Phosphorylation of MET and MET amplification is associated with lung adenocarcinoma.

The cross-talk and balance between HGF/c-Met signal pathways are critical and necessary in the development of new therapies for lung cancer.

Our results indicated that the overexpression of c-Met gene played an important role in the progression and development of small cell lung cancer.

Expressed in most neuroendocrine tumors of lung. Coexpression of PAX5 with c-Met or phosphorylated c-Met was present in most of the atypical carcinoids, SCLCs, and large cell neuroendocrine carcinomas.

There is a positive correlation between the EGFR and c-Met protein expression and the differentiation of non-small cell lung cancer.

EGFR and c-Met may interact in a synergistic manner in the oncogenesis and development of non-small cell lung cancer. expressions were higher in smokers than in nonsmokers.

MET amplification is associated with non-small cell lung cancer.

Data show that showed that miR-130a, expressed at low level in lung cancer cell lines, by targeting MET was able to reduce TRAIL resistance in non-small cell lung cancer (NSCLC) cells through the c-Jun-mediated downregulation of miR-221 and miR-222.

MET mutation is associated with treatment response in non-small cell lung cancer.

Met overexpression, but not met mutation, correlates with progression of non-small cell lung cancer.

suggest that abnormality of the HGF/MET pathway occurs during the course of progression from non-invasive to invasive pulmonary adenocarcinoma

The structure of the MET receptor, the activated pathways, the main genomic anomalies in lung cancer & the development of MET inhibitors are reviewed. Review.

High c-MET/phospho-MET protein expression and MET gene copy number is associated with nonsquamous non-small cell lung carcinomas.

Increased MET copy number and MET overexpression are negative prognostic factors for surgically resected in non-small cell lung cancer

MET gene copy number by silver in situ hybridization and protein expression is not associated with non-small cell lung carcinomas.

In small cell lung cancer and neuroendocrine tumors MET mutations are relatively rare; detected mutations were located in the juxtamembrane domain and were of no functional relevance as they did not influence c-Met phosphorylation

findings show that miR-34b may play an important role in non-small cell lung cancer progression; miR-34b downregulates Met, with subsequent changes of downstream p53 and Mdm2, and inversely p53 upregulates miR-34b in a feedback loop

Results document MET mutations in anaplastic lymphoma kinase-rearranged (ALK+) lung adenocarcinomas. The pathogenic role of these MET mutations is not entirely clear.

miR-27a regulates MET, EGFR, and Sprouty2 in lung cancer.

Data show that the expression of miR-449a was reciprocally correlated with c-Met in non-small cell lung cancer (NSCLC) tissues.

data suggest that the c-Met-N375S sequence variant may not play a significant role in cancer susceptibility and the prognosis of lung cancer patients

Amplication of the MET protooncogene has been associated with resistance to gefitinib or erlotinib in about 5% of patients, initially responsive to the drug. Somatic mutations in the TK domain of MET have been described in non-small cell lung cancer

evaluated mutations in four driver genes, epidermal growth factor receptor (EGFR), Kirsten ras oncogene (KRAS), c-MET, and echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), in Chinese lung adenocarcinoma patients

activation through phosphorylation is assosiated with micropapillary pattern and small cluster invasion in lung adenocarcinoma

Data indicate that coexistence of EML4-ALK fusion or ALK copy number increase and EGFR, MET, and KRAS mutations in tumor tissue from two treatment-naive Chinese non-small cell lung cancer (NSCLC) patients.

MET gene copy number gain is associated with stage I lung adenocarcinomas.

MET dependent epithelial-to-mesenchymal transition plays an important role in the adverse clinical behavior of small cell lung cancers.

Collectively, these findings suggest that the combinatorial inhibition of MET and Top1 is a potentially efficacious treatment strategy for Small cell lung cancer .

Increased MET gene copy number is associated with response to chemotherapy in lung adenocarcinoma.

Data shows that MET and RON are regulated by PAX8 in non-small cell lung cancer.

Increased MET gene copy number or protein expression was significantly associated with poorer survival in patients with surgically resected non-small cell lung cancer.

CMET overexpression and CMET amplification are commonly found in non-small cell lung cancer (NSCLC) brain metastases and may represent a promising therapeutic target.

Therefore, these results suggest that SB365 is good candidate as a natural product for use in the treatment of Met-amplified non-small cell lung cancers

Single-nucleotide polymorphism rs41736 located in MET was significantly associated with prognosis of small cell lung cancer Chinese patients.

The aim was to quantify the level of serum MET DNA, analyze its diagnostic value, and provide a novel biomarker for lung cancer.

Two thirds (67%) of lung cancers do not have gains in MET gene copy numbers, whereas 3% show a clear-cut high-level amplification

HGF mediated resistance to alectinib, but not to crizotinib, via the MET signal, that alectinib activated the MET signal in ALK-positive non-small cell lung cancer.

expression of HGFalpha or cMet was closely correlated with VEGFC, lymphatic microvessel density and metastases of lymph nodes, indicating HGFalpha, cMet and VEGFC may perform important and collaborative actions in lymphangiogenesis and lymphatic metastasis of primary non-small-cell lung cancer

tumor-suppressive miR206 inhibited dual signaling networks activated by MET and EGFR in lung squamous cell carcinoma.

These results demonstrated that plasma s-Met is a sensitive and reliable marker to detect c-Met overexpression in lung cancers, and it is independent of tumor volume.

MET gene may be useful in predicting shortened PFS and OS after Gefitinib treatment in lung adenocarcinoma. The correlation between MET gene status and clinical outcomes for EGFR-TKI should be further evaluated using large scale samples.

MET overexpression is more frequent than MET high gene copy number, particularly in high grade non-small cell lung cancers

Upregulation of EGFR and c-Met is associated with epithelial mesenchymal transition in response to increased matrix rigidity in pulmonary adenocarcinoma.

MET protein overexpression and MET gene amplification is associated with non-small cell lung cancer.

our study provided a miRNA-gene regulatory network in lung cancer metastasis and further demonstrated the roles of miR-206 and MET in this process, which enhances the understanding of the regulatory mechanism in lung cancer metastasis.

only miR-34a was prognostic for RFS (RR, 11.5; P = 0.027). miR-34a expression was inversely correlated with that of c-MET and CDK6 in non-small cell lung cancer , and had prognostic significance for RFS, especially in adenocarcinoma patients.

Overexpression of miR-200a in non-small lung cancer cells significantly downregulates both EGFR and c-Met levels and severely inhibits cell migration and invasion.

MET mutations leading to exon 14 skipping were identified in eight (22%) of 36 cases of pulmonary sarcomatoid carcinoma.

TNS1, MET, and TRKC tyrosine-phosphorylated proteins are upregulated during epithelial-mesenchymal transition induced with TGF-beta, and predict the outcome in lung adenocarcinoma patients.

TPST1 was significantly negatively correlated with the expression of cMet in lung cancer and may be a negative prognostic biomarker of lung cancer.

MicroRNA-31 inhibits lung adenocarcinoma stem-like cells via down-regulation of MET-PI3K-Akt signaling pathway

HGF and its receptor, cMET, are antagonized in human lung cancer cells treated with YangZheng XiaoJi

Data show that inhibition of ATP binding cassette subfamily B member 1 (ABCB1) might be a novel therapeutic strategy for non-small cell lung cancer (NSCLC) patients with acquired resistance to proto-oncogene proteins c-met (MET) inhibitors.

High MET Gene copy number and protein expression is associated with nodal metastases in Non-Small-Cell lung cancer.

Data reported evidence that the SNPs rs76322625 and rs41281081 in the MET 3'UTR are involved in the occurrence of non-small-cell lung cancer. They are respectively regulated by miR-335 and miR-1026 causing up-regulation of MET in patients.

Results showed that c-MET expression is increased in drug-resistant lung cancer cell lines and its inhibition reversed it confirming that activated c-MET is one of the mechanisms by which cells acquire resistance to cytotoxic anticancer drugs.

MET gene amplification and MET receptor activation are not sufficient to predict a positive response of non small cell lung cancers cells to a cocktail of MET and EGFR inhibitors.

MET copy number Gain is associated with response to crizotinib therapy in lung Adenocarcinoma.

MET Exon 14 mutations in Non-Small-Cell lung cancer Are Associated With Advanced Age and Stage-Dependent MET Genomic Amplification and c-Met Overexpression.

Results indicate that miR-329 played a pivotal role in lung cancer through inhibiting cell proliferation, migration, invasion, and promoting apoptosis by targeting oncogenic MET.

Lymphovascular invasion and c-MET overexpression might be associated with poor prognosis in stage IB non-small-cell lung cancer patients

Data show that MET is the direct target of miR-206 in lung cancer cells.

MET exon 14 skipping occurs with an approximately 5% frequency in Non-small cell lung cancers and is seen in both squamous and adenocarcinoma histology. Patients whose cancers have MET exon 14 skipping can respond well to MET inhibitors. Molecular testing for MET exon 14 skipping should be performed on all lung cancers because this is a targetable alteration

c-Met may have a role in response to EGFR-TKI treatment in advanced non-small cell lung cancer

MET exon 14 skipping was detected in 1.3% (23/1770) of the Chinese patients with Non-Small Cell lung cancer (NSCLC). MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC.

study presents the unique characteristics of MET exon 14 mutations in Chinese patients with non-small-cell lung cancer (NSCLC); found no significant relationships among the mutation, MET amplification, and MET overexpression; MET exon 14 mutation per se may not be sufficiently robust for use in defining a subset of NSCLCs

Met inhibition is an effective strategy to overcome resistance of certain EGFR-mutated non-small cell lung carcinomas with Met amplification to protein kinase inhibitors.

High Met expression is associated with Non-Small-Cell lung cancer.

c-Met overexpression, HER-2 gene amplification, and SPTBN1-ALK gene fusion can coexist in lung adenocarcinoma and may become a potential biomarker of cancer refractory to crizotinib, chemotherapy, and radiotherapy as well as of a relatively poor prognosis.

ABBV-399 represents a novel therapeutic strategy to deliver a potent cytotoxin to c-Met-overexpressing tumor cells enabling cell killing regardless of reliance on MET signaling. ABBV-399 has progressed to a phase I study where it has been well tolerated and has produced objective responses in c-Met-expressing non-small cell lung cancer (NSCLC) patients.

MET amplification is associated with Response to Crizotinib in non-Small Cell lung cancer.

MET Y1230C mutation is associated with Resistance to Crizotinib in non-Small Cell lung cancer.

MET Exon 14-Positive is associated with Brain Metastases in non-Small Cell lung cancer.

although the juxtamembrane mutations of MET do not affect its known proteolytic cleavages, the R970C MET variant favors calpain dependent proteolytic cleavage in lung cancer cells.

MET is overexpressed and activated preferentially along the peripheral invasive front of the tumor and on tumor cells spreading through air spaces in non-small cell lung carcinoma.

Study provides evidence that AXL and MET are associated with cell proliferation and metastasis in lung cancer, and the crosstalk between these receptors affects tumor progression.

The MET mutation is involved in the pathogenesis of EGFR-mutant lung cancer.

MET Gene Amplification and Overexpression is associated with Non-Small-Cell lung cancer.

There are 2 categories of MET gene amplification in lung cancer patients, de novo and that secondary to TKI therapy. These patients can benefit from MET inhibitor therapy. Dual mechanisms of resistance, EGFR T790M mutation and c-MET amplification after TKI therapy, may suggest a poor prognosis.

Studies provide evidence that MET amplification in non-small cell lung cancer is implicated in acquired resistance to EGFR inhibitors and has been reported in approximately one-fifth of cases with EGFR inhibitor resistance. [review]

Dual MET and SMO Inhibitors are potent antiproliferative agents in EGFR-Tyrosine kinase inhibitors resistant human non small cell lung cancer.

Selective MET tyrosine kinase inhibitor SAR125844 has significant antitumour activity in patients with MET-amplified non-small cell lung carcinoma.

Distinct MET protein localization is associated with MET exon 14 mutation types in patients with non-small-cell lung cancer

The expression of C-Met and HER2 protein in lung adenocarcinoma is highly correlated, and whether it is synergistic in the targeted therapy of lung adenocarcinoma deserves further study.

The authors reconfirmed EGFR mutation as a strong predictive marker of Non-Small-Cell lung cancer. However, c-MET positivity was not associated with response or progression-free survival, although c-MET overexpression correlated with some clinical characteristics.

EGFR T790M mutation and cMET amplification are main mechanisms leading to EGFR TKI resistance in lung adenocarcinoma.

Data show that Kruppel like factor 4 (KLF4) was overexpressed in met proto-oncogene protein (c-Met)-overexpressing non-small-cell lung cancer (NSCLC) cells and tissues.

Study found that TIGAR and Met protein expression was positively correlated with late stages of lung cancer. Patients with high co-expression of TIGAR and Met presented a significantly worse survival. In addition, Met signaling pathway is involved in TIGAR-induced invasion and metastasis.

X-ray irradiation induced the aggregation of lipid rafts and the clustering of c-Met and c-Src to lipid rafts through both lipid raft-dependent and lipid raft-independent mechanisms. The lipid raft-dependent activation of c-Met and its downstream pathways played an important role in the development of radiation resistance in non-small cell lung cancer cells mediated by c-Met.

HGF/c-Met regulates expression of SAE2 and cirRNA CCDC66 to increase epithelial-to-mesenchymal transition and drug resistance of lung adenocarcinoma cells.

We show that MET activation promotes the expression of several negative checkpoint regulators of the immunoresponse, including PD-L1. In addition, we report inactivation of JAK2 in lung cancer cells that prevented the response to IFNgamma.

MET Exon 14 Skipping mutations in Non-small Cell lung cancer

This review summarizes the molecular mechanisms responsible for MET exon 14 skipping as well as the consequences of the loss of this exon on receptor activity. We also describe the clinical characteristics of patients with METDelta14 mutations. Finally, we address the issues related to the detection of these mutations in lung cancer, and the need to anticipate resistance to MET inhibitors. [review]

Study have established MET-amplified non-small cell lung cancer (NSCLC) cell lines that showed acquired resistance to capmatinib and evaluated its resistance mechanisms. Results demonstrated that capmatinib-resistant NSCLC cells were dependent on alternative pathway activation.

KRAS mutation is a recurrent mechanism of primary and secondary resistance to MET tyrosine kinase inhibitors in METex14 lung cancers.

MET-altered carcinomas of the lung differ clinically and genetically. MET exon 14 skipping mutations represent an early driver mutation. MET amplifications occur usually in the background of other strong genetic events and therefore MET amplifications should be interpreted in the context of each tumor's genetic background.

High MET expression is associated with metastasis and tumor growth of lung adenocarcinoma.

We identified that PTEN loss and increased MET copy number may predict an unfavorable survival in mutated-EGFR non-small-cell lung cancer patients.

We found that both protein and gene expression levels of serum cMET, HGF and EGFR were higher in patients with lung cancer. We suggest that protein and gene expression levels of c-MET in patients with lung cancer will lead to targeted therapies as a new biomarker.

MET IHC Is a Poor Screen for MET Amplification or MET Exon 14 mutations in lung Adenocarcinomas: Data from a Tri-Institutional Cohort of the lung cancer mutation Consortium.

This is the first study from the Indian subcontinent to identify the frequency of ROS-1 re-arrangements and MET amplification in the Indian lung adenocarcinoma population. c-MET protein expression was identified in 33.33%, and ROS-1 protein expression was detected in 3.33% cases.

exon 14 skipping mutations and gene amplification in lung cancer

Fusion affecting MET gene was detected in unselected lung adenocarcinomas in oncogenic driver-negative lung adenocarcinomas from Chinese population.

MET exon 14 skipping mutation is associated with pulmonary sarcomatoid carcinoma.

Co-occurring Alterations in the RAS-MAPK pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping mutation-Positive lung cancer.

Highly accurate DNA-based detection and treatment results of MET exon 14 skipping mutations in lung cancer.

Elucidation of the relationships of MET protein expression and gene copy number status with PD-L1 expression and the immune microenvironment in non-small cell lung cancer.

These results address an unmet need for targeted therapy in people with lung cancers with MET exon 14 alterations.

Progress on treatment of MET signaling pathway in non-small cell lung cancer.

MET amplification results in heterogeneous responses to osimertinib in EGFR-mutant lung cancer treated with erlotinib.

Loss of histone lysine methyltransferase EZH2 confers resistance to tyrosine kinase inhibitors in non-small cell lung cancer.

Detection of MET Exon 14 Skipping Alterations in lung cancer Clinical Samples Using a PCR-Based Approach.