Mesenchymal-epithelial Transition Factor Gene Research Articles

EE160 Tepotinib for the Treatment of Adult Patients with Metastatic Non-Small Cell Lung Cancer Harboring METEX14 Skipping Alterations: A US Cost-Effectiveness Analysis

This study compared the cost-effectiveness, from the US Medicare perspective, of tyrosine kinase inhibitors tepotinib and capmatinib for treating line-agnostic adult patients with metastatic non-small cell lung cancer (mNSCLC) harboring mesenchymal-epithelial transition factor gene exon 14 (METex14) skipping alterations.

Correlation of c-MET expression with clinical characteristics and the prognosis of colorectal cancer

The proto-oncogene c-MET (mesenchymal-epithelial transition factor gene) plays a critical role in cellular proliferation, survival, migration, and invasion in cancers. The aim of this study is to explore the relationship between c-MET expression and the clinicopathological characteristics of colorectal cancer (CRC) patients. A total of 337 enrolled patients were collected in present study. Here, the c-MET and EGFR expression were detected by immunohistochemistry (IHC). The mutational statuses of KRAS in exons 2, 3, and 4, NRAS in exons 2, 3, and 4, and BRAF in exon 15 from formalin-fixed sections were detected by direct DNA sequencing. Our results showed that high c-MET expression was significantly associated with tumor perineural invasion (P=0.007) and gender (P=0.016). High level c-MET expression (c-MET-high) in the primary tumors was observed in 68.2% of patients. In the 337 enrolled patients, 43.2% of patients had KRAS mutations, 3.3% of patients had NRAS mutations, and 4.7% of patients had BRAF mutations. However, KRAS, NRAS, and BRAF gene mutations had no association with c-MET protein levels in primary tumors. Additionally, c-MET protein expression had a strong correlation with EGFR expression (P=0.002). The survival time was not significantly longer for patients with c-MET-high primary tumors than for those with c-MET-low primary tumors. c-MET immunohistochemistry was significantly higher in primary tumors with perineural invasion, female gender, and EGFR high expression. However, c-MET-high in the primary tumors was not significantly associated with longer survival compared with c-MET-low tumors. Further studies are required to investigate c-MET as potential molecular marker of progression and to test the possibility of its incorporation as a new therapeutic target.

Mesenchymal epithelial transition factor regulates tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells through down-regulation of cyclin B1.

Tumor necrosis factor-related apoptotic induction ligand can induce cell apoptosis in various tumor cells. However, many cancer cells are resistant to tumor necrosis factor-related apoptotic induction ligand. Therefore, overcoming the tumor necrosis factor-related apoptotic induction ligand resistance makes it possible for tumor necrosis factor-related apoptotic induction ligand-based anti-cancer therapies. In this study, we took mesenchymal epithelial transition factor as the research target to study its role in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma. Mesenchymal epithelial transition factor gene has been proved to be an effective predictor of recurrence after hepatocellular carcinoma resection. The expression of mesenchymal epithelial transition factor and cyclin B1 were measured in tumor necrosis factor-related apoptotic induction ligand-resistant and non-resistant hepatocellular carcinoma tissues. Cyclin B1-knockdown and cyclin B1-overexpression hepatocellular carcinoma cells were treated with tumor necrosis factor-related apoptotic induction ligand; mesenchymal epithelial transition factor knockout, mesenchymal epithelial transition factor re-introduction and cyclin B1 restored in hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand were established. And MTT, bromodeoxyuridine, flow cytometry and western blotting were performed to evaluate the effect of mesenchymal epithelial transition factor and cyclin B1 on hepatocellular carcinoma cells treated with tumor necrosis factor-related apoptotic induction ligand. In addition, subcutaneous tumor transplantation in nude mice was conducted to access the effect of mesenchymal epithelial transition factor and cyclin B1 on tumor formation in vivo. In conclusion, cyclin B1 enhanced the cell growth and inhibited apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells. And mesenchymal epithelial transition factor promoted the cell growth and apoptosis in tumor necrosis factor-related apoptotic induction ligand-resistant hepatocellular carcinoma cells by regulating cyclin B1. Therefore, mesenchymal epithelial transition factor regulates the cyclin B1 to regulate tumor necrosis factor-related apoptotic induction ligand resistance in hepatocellular carcinoma cells. Our results suggest a novel molecular mechanism for regulating tumor necrosis factor-related apoptotic induction ligand resistance, which might be helpful to select drug targets in the treatment of liver cancer.

Progress on Mechanism of MET Gene Mutation and Targeted Drugs in Non-small Cell Lung Cancer

间质-上皮细胞转化因子（mesenchymal-epithelial transition factor, MET）基因是非小细胞肺癌（non-small cell lung cancer, NSCLC）的一种重要肿瘤驱动基因，针对MET 14外显子的跳跃突变的靶向治疗药物给患者带来新的希望。目前已经上市或者即将上市的MET抑制剂包括：克唑替尼、卡博替尼、沃利替尼和Tepotinib等。MET抑制剂的客观缓解率较高，并且安全性良好。但是，MET抑制剂的耐药不可避免，因此需要重视对于耐药机制的研究。肝细胞生长因子（hepatocyte growth factor, HGF）/MET信号通路抑制剂与其他药物的联合应用，对于抑制和逆转耐药可能发挥重要作用。

C-MET Overexpression in Colorectal Cancer: A Poor Prognostic Factor for Survival

IntroductionIncreased mesenchymal-epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumor progression and is a new potential drug target for several types of cancers. In the present study, we investigated the incidence of c-MET overexpression and its prognostic significance in patients with colorectal cancer (CRC). Patients and MethodsWe retrospectively reviewed the data from 255 stage IV CRC patients who had results from a c-MET immunohistochemical test at Samsung Medical Center. We explored the relationships between c-MET overexpression and clinicopathological features and survival. ResultsPrimary tumor sites were 67 right-sided colon, 98 left-sided colon, and 90 rectum. Forty-two patients (16.7%) had poorly differentiated or mucinous carcinoma. Among the 255 patients, 39 (15.3%) exhibited c-MET overexpression. There was no significant difference in the prevalence of c-MET overexpression according to primary site, histologic differentiation, molecular markers, or metastatic sites. In a comparison of the tumor response to first-line chemotherapy according to the level of c-MET expression, we found no significant difference in either partial response or disease control rate. In the survival analysis, patients with c-MET overexpression had significantly shorter overall survival (39 vs. 27 months; P = .018) and progression-free survival (PFS) during bevacizumab treatment (10 vs. 7 months; P = .024). Conclusionc-MET overexpression, which was detected in 39 CRC patients (15.3%) irrespective of primary sites or molecular markers, indicated a poor survival prognosis and predicted shorter PFS during bevacizumab treatment in patients with CRC. Further studies are warranted to elucidate the value of c–MET-targeted therapy in CRC patients.

Expression and significance of MET gene in non-small cell lung cancer

Objective To detect the mRNA expression of mesenchymal-epithelial transition factor (MET) gene in patients with non-small cell lung cancer (NSCLC), and to investigate the relationship and clinical significance between the mRNA expression of MET gene and clinical pathological characteristics. Methods From June 2011 to November 2013, 48 patients with pathologically confirmed NSCLC in Chinese People′s Liberation Army General Hospital were selected. All patients included in the study were not treated before surgery. The branched DNA liquid chip technology was used to detect mRNA expression of MET gene in tumor tissues. The relationship between mRNA expression of MET gene and clinical pathological characteristics was analyzed. Results The constituent ratios of low, moderate and high mRNA expression level of MET gene were 22.9%, 50.0% and 27.1% respectively, mainly for the moderate expression. The mRNA expression of MET gene was related to the pathologic type (χ2=7.183, P=0.020) and TNM stage (χ2=24.566, P=0.017) of the patients; but it was not related to the gender (χ2=0.566, P=0.754), age (χ2=1.857, P=0.395), smoking history (χ2=4.959, P=0.084), degrees of differentiation (χ2=5.749, P=0.067), lymph node metastasis (χ2=1.631, P=0.442) and distant metastasis (χ2=4.261, P=0.119). Conclusion mRNA expression of MET gene is more likely to present moderate and higher level in NSCLC patients. MET gene can also be used as a biomarker for judging tumor pathological type. Key words: Carcinoma, non-small-cell lung; RNA, messenger; Mesenchymal-epithelial transition factor

C-MET immunostaining in colorectal carcinoma is associated with local disease recurrence.

BackgroundIncreased mesenchymal–epithelial transition factor gene (c-MET) expression in several human malignancies is related to increased tumour progression. The aim of the present study is to explore the relationship between immunohistochemical expression of c-MET in colorectal carcinoma (CRC) and the clinicopathological characteristics and follow up data, to compare the expression of c-MET in primary CRC and its metastasis in lymph nodes and to test its validity as independent prognostic factor.MethodsHundred and thirty-five archival CRC and nodal metastases samples were collected from King Abdulaziz University Hospital, Saudi Arabia. Tissue microarrays were constructed and immunohistochemistry was done to detected c-MET protein expression. Appropriate statistical analysis was performed.ResultsHigh c-MET immunostaining was significantly associated with tumour size larger than 5 cm (p < 0.003) and in left colon subsite (p < 0.05). There was no significant correlation between c-MET protein expression and age, sex, degree of differentiation, tumour invasion, presence of nodal metastasis, lymphovascular invasion, status of surgical resection margin, or presence of distant metastasis. Furthermore, no association between c-MET protein expression and disease free survival. High protein expression of c-MET is associated with the incidence of local disease recurrence (p < 0.012).Conclusionc-MET is a new promising target that may help in understanding the pathogenesis of CRC, and to be used as independent prognostic biomarker to predict local disease recurrence in CRC. Further molecular in vitro and in vivo studies are required to pursue c-MET as potential molecular marker of metastases and test the possibility of its incorporation as a new targeted therapeutic target.

MET overexpression as a hallmark of the epithelial-mesenchymal transition (EMT) phenotype in colorectal cancer.

334 Background: Dysregulation of the proto-oncogene MET (mesenchymal-epithelial transition factor gene) has been implicated in tumorigenesis and correlates with worse survival and chemo/radio-resistance in colorectal cancer (CRC). EMT has been identified as a dominant molecular characteristic of a subset of CRC tumors and represents a key feature in the developing colorectal taxonomy. The purpose of this study was to compare protein expression of MET with protein/gene expression of EMT markers and other clinicopathological characteristics, and to evaluate its impact on overall survival (OS). Methods: We performed an exploratory analysis of 590 CRC samples using data from The Cancer Genome Atlas. Fisher-exact test and Pearson’s method was used to determine the relationship between MET protein expression, clinicopathological characteristics and EMT marker protein expression by reverse-phase protein array (RPPA) and EMT-associated gene expression by RNA-sequencing. Regression tree method was applied to find the best cutoff point for MET using patients with available survival data. Overall survival (OS) was estimated non-parametrically using Kaplan-Meier curve and log-rank test was used to evaluate hazard ratio. Results: MET expression by RPPA did not correlate with traditional clinicopathologic characteristics. MET was overexpressed in 17% of CRC tumors and was significantly associated with OS (HR 2.92; 95% CI: 1.45 - 5.92). Correlation analysis of MET levels with gene expression of EMT markers AXL, CDH1, FGFR1, SNAIL, TWIST1/2, VIM, SLUG, ZEB1/2, FN1 demonstrated that the highest quartile of MET protein expression was associated with a 1.5 fold increase in ZEB1 (p = 0.002), a 1.4 fold increase in AXL (p = 0.005) and ZEB2 (p = 0.008), and a 1.3 fold increase in VIM (p = 0.02). MET expression also correlated strongly with protein expressions of SNAIL (transcription factor for EMT) (r = 0.96) and ERCC1 (r = 0.83) (a marker for oxaliplatin chemo-resistance). Conclusions: Increased MET protein expression is seen in 17% of CRC tumors and strongly correlates with a molecular EMT phenotype and poor survival in patients with CRC. MET protein expression may be a surrogate biomarker for this unique subset of CRC.

Role of HGF/MET axis in resistance of lung cancer to contemporary management.

Lung cancer is the number one cause of cancer related mortality with over 1 million cancer deaths worldwide. Numerous therapies have been developed for the treatment of lung cancer including radiation, cytotoxic chemotherapy and targeted therapies. Histology, stage of presentation and molecular aberrations are main determinants of prognosis and treatment strategy. Despite the advances that have been made, overall prognosis for lung cancer patients remains dismal. Chemotherapy and/or targeted therapy yield objective response rates of about 35% to 60% in advanced stage non-small cell lung cancer (NSCLC). Even with good initial responses, median overall survival of is limited to about 12 months. This reflects that current therapies are not universally effective and resistance develops quickly. Multiple mechanisms of resistance have been proposed and the MET/HGF axis is a potential key contributor. The proto-oncogene MET (mesenchymal-epithelial transition factor gene) and its ligand hepatocyte growth factor (HGF) interact and activate downstream signaling via the mitogen-activated protein kinase (ERK/MAPK) pathway and the phosphatidylinositol 3-kinase (PI3K/AKT) pathways that regulate gene expression that promotes carcinogenesis. Aberrant MET/HGF signaling promotes emergence of an oncogenic phenotype by promoting cellular proliferation, survival, migration, invasion and angiogenesis. The MET/HGF axis has been implicated in various tumor types including lung cancers and is associated with adverse clinicopathological profile and poor outcomes. The MET/HGF axis plays a major role in development of radioresistance and chemoresistance to platinums, taxanes, camtothecins and anthracyclines by inhibiting apoptosis via activation of PI3K-AKT pathway. DNA damage from these agents induces MET and/or HGF expression. Another resistance mechanism is inhibition of chemoradiation induced translocation of apoptosis-inducing factor (AIF) thereby preventing apoptosis. Furthermore, this MET/HGF axis interacts with other oncogenic signaling pathways such as the epidermal growth factor receptor (EGFR) pathway and the vascular endothelial growth factor receptor (VEGFR) pathway. This functional cross-talk forms the basis for the role of MET/HGF axis in resistance against anti-EGFR and anti-VEGF targeted therapies. MET and/or HGF overexpression from gene amplification and activation are mechanisms of resistance to cetuximab and EGFR-TKIs. VEGF inhibition promotes hypoxia induced transcriptional activation of MET proto-oncogene that promotes angiogenesis and confers resistance to anti-angiogenic therapy. An extensive understanding of these resistance mechanisms is essential to design combinations with enhanced cytotoxic effects. Lung cancer treatment is challenging. Current therapies have limited efficacy due to primary and acquired resistance. The MET/HGF axis plays a key role in development of this resistance. Combining MET/HGF inhibitors with chemotherapy, radiotherapy and targeted therapy holds promise for improving outcomes.

CMET and Phospho-cMET Protein Levels in Breast Cancers and Survival Outcomes

To evaluate cMET (mesenchymal-epithelial transition factor gene) and phospho-cMET (p-cMET) levels in breast cancer subtypes and its impact on survival outcomes. We measured protein levels of cMET and p-cMET in 257 breast cancers using reverse phase protein array. Regression tree method and Martingale residual plots were applied to find best cutoff point for high and low levels. Kaplan-Meier survival curves were used to estimate relapse-free (RFS) and overall (OS) survival. Cox proportional hazards models were fit to determine associations of cMET/p-cMET with outcomes after adjustment for other characteristics. Median age was 51 years. There were 140 (54.5%) hormone receptor (HR) positive, 53 (20.6%) HER2 positive, and 64 (24.9%) triple-negative tumors. Using selected cutoffs, 181 (70.4%) and 123 (47.9%) cancers had high levels of cMET and p-cMET, respectively. There were no significant differences in mean expression of cMET (P < 0.128) and p-cMET (P < 0.088) by breast cancer subtype. Dichotomized cMET and p-cMET level was a significant prognostic factor for RFS [HR: 2.44, 95% confidence interval (CI): 1.34-4.44, P = 0.003 and HR: 1.64, 95% CI: 1.04-2.60, P = 0.033] and OS (HR: 3.18, 95% CI: 1.43-7.11, P = 0.003 and HR: 1.92, 95% CI: 1.08-3.44, P = 0.025). Within breast cancer subtypes, high cMET levels were associated with worse RFS (P = 0.014) and OS (P = 0.006) in HR-positive tumors, and high p-cMET levels were associated with worse RFS (P = 0.019) and OS (P = 0.014) in HER2-positive breast cancers. In multivariable analysis, patients with high cMET had a significantly higher risk of recurrence (HR: 2.06, 95% CI: 1.08-3.94, P = 0.028) and death (HR: 2.81, 95% CI: 1.19-6.64, P = 0.019). High p-cMET level was associated with higher risk of recurrence (HR: 1.79, 95% CI: 1.08-2.95.77, P = 0.020). High levels of cMET and p-cMET were seen in all breast cancer subtypes and correlated with poor prognosis.