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Targeting the hepatocyte growth factor-cMET axis in cancer therapy.

ABSTRACT: The hepatocyte growth factor (HGF) and its receptor, the transmembrane tyrosine kinase cMET, promote cell proliferation, survival, motility, and invasion as well as morphogenic changes that stimulate tissue repair and regeneration in normal cells but can be co-opted during tumor growth. MET overexpression, with or without gene amplification, has been reported in a variety of human cancers, including breast, lung, and GI malignancies. Furthermore, high levels of HGF and/or cMET correlate with poor prognosis in several tumor types, including breast, ovarian, cervical, gastric, head and neck, and non-small-cell lung cancers. Gene amplification and protein overexpression of cMET drive resistance to epidermal growth factor receptor family inhibitors, both in preclinical models and in patients. It is increasingly apparent that the HGF-cMET axis signaling network is complex, and rational combinatorial therapy is needed for optimal clinical efficacy. Better understanding of HGF-cMET axis signaling and the mechanism of action of HGF-cMET inhibitors, along with the identification of biomarkers of response and resistance, will lead to more effective targeting of this pathway for cancer therapy.

SUBMITTER: Blumenschein GR

PROVIDER: S-EPMC3434988 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Hepatocyte Growth Factor/cMET Pathway Activation Enhances Cancer Hallmarks in Adrenocortical Carcinoma.

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| S-EPMC4592476 | biostudies-literature

Targeting the Hepatocyte Growth Factor and c-Met Signaling Axis in Bone Metastases.

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| S-EPMC6359064 | biostudies-literature

Targeting the HGF-cMET Axis in Hepatocellular Carcinoma.

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| S-EPMC3626399 | biostudies-literature

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| S-EPMC4156285 | biostudies-literature

Progress of antibody-based inhibitors of the HGF-cMET axis in cancer therapy.

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| S-EPMC5382561 | biostudies-literature

Hepatocyte Growth Factor/C-Met Axis in Thyroid Cancer: From Diagnostic Biomarker to Therapeutic Target.

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| S-EPMC5391983 | biostudies-literature

Hepatocyte growth factor and soluble cMet levels in plasma are prognostic biomarkers of mortality in patients with severe acute kidney injury.

Project description:BackgroundHepatocyte growth factor (HGF)/cMet pathway is necessary for repair and regeneration following acute kidney injury (AKI). We evaluated the clinical potential of plasma HGF and soluble cMet as prognostic biomarkers for severe AKI requiring continuous renal replacement therapy (CRRT).MethodsOne hundred thirty-six patients with severe AKI who participated in the VENUS (volume management under body composition monitoring in critically ill patients on CRRT) trial between 2017 and 2019 were enrolled in this study. We investigated associations between plasma HGF and cMet concentrations and all-cause mortality.ResultsPlasma HGF and soluble cMet levels were positively correlated. Patients were divided into three groups based on their HGF and soluble cMet concentrations. The day D 0, D2, and D7 highest concentration HGF groups had significantly higher in-hospital mortality after adjusting for sex, body mass index, Acute Physiology and Chronic Health Evaluation II, and age-adjusted Charlson comorbidity index score, especially on D7 (hazard ratio, 4.26; 95% confidence interval, 1.71-10.62; p = 0.002). D7 soluble cMet level was also associated with mortality. Receiver operating characteristic curve analysis indicated that D7 HGF and soluble cMet levels were best at predicting mortality. Addition of plasma HGF and soluble cMet to conventional prognostic indices significantly improved the predictive value for mortality on D7. However, plasma HGF and soluble cMet were not associated with fluid status.ConclusionPlasma HGF and soluble cMet levels were significant predictors of the outcomes of severe AKI patients undergoing CRRT. There was no correlation between plasma HGF and soluble cMet levels and fluid balance.

| S-EPMC8685369 | biostudies-literature

Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy.

Project description:TGF-β pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-β (TGF-β) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-β related functional contexts. This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression and promotion by TGF-β. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. The TGF-β inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.

| S-EPMC3825194 | biostudies-literature

Assessment of hepatocyte growth factor in ovarian cancer mortality.

Project description:BackgroundInvasive ovarian cancer is a significant cause of gynecologic cancer mortality.MethodsWe examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths).ResultsThe strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10(-5)) and with overall variation in HGF (gene-level test, P = 3.7 × 10(-4)). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r(2) = 0.96 with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10(-3); Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10(-5)] and suggested genotype correlation with reduced HGF mRNA levels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87).ConclusionsWe conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression.ImpactOur study shows the utility of multiple data types and multiple data sets in observational studies.

| S-EPMC3153603 | biostudies-literature

Resistance to targeted cancer drugs through hepatocyte growth factor signaling.

Project description:Cancer therapeutics that target a signaling pathway to which the cancer cells are addicted can deliver dramatic initial responses, but resistance is nearly always inevitable. A variety of mechanisms that cancer cells employ to escape from targeted cancer drugs have been described. We review here the role of Hepatocyte Growth Factor (HGF) and its receptor MET in drug resistance. We present data demonstrating that HGF can confer resistance to a number of kinase inhibitors in a variety of cancer cell lines and discuss our results in relation to the findings of others. Together, these data point at a major role for HGF/MET signaling in resistance to a variety of targeted cancer drugs.

| S-EPMC4615055 | biostudies-literature

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