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Crosstalk between the MET and EGFR pathways. HGF: hepatocyte growth factor; EGF: epidermal growth factor.
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The hepatocyte growth factor (HGF): MET axis is a ligand-mediated receptor
tyrosine kinase pathway that is involved in multiple cellular functions, including proliferation,
survival, motility, and morphogenesis. Aberrancy in the HGF/MET pathway has been
reported in multiple tumor types and is associated with tumor stage and prognosis. Thus,
targeti...
Context in source publication
Context 1
... in the last decade has revealed that crosstalk between the MET and EGFR pathways on cell's survival, proliferation and migration (Figure 2) may play a key role in enhancing cancer cell development and progression in NSCLC. Preclinical studies have shown the synergistic effect between HGF and epidermal growth factor (EGF) on cancer cell proliferation and downstream activation of signal transduction, and the potential application of both MET and EGFR TKIs in a synergistic fashion in cancer treatment [100,101]. ...
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Background The MET tyrosine kinase and its ligand, hepatocyte growth factor (HGF) also known as scatter factor, are associated with tumourigenesis and metastasis by promotion of scattering, proliferation, angiogenesis, motility and invasion. ASLAN-002 is a potent inhibitor of MET as well as related kinases. A phase I dose escalation study was condu...
Citations
... Supporting this theory, administering HGF to mice has demonstrated modulation of hepatic mRNA expression of enzymes involved in glucose and lipid metabolism, thereby mimicking the effects of insulin (Fafalios et al., 2011). Moreover, the HGF-Met signaling pathway indirectly supports glucose homeostasis by enhancing β-cell proliferation and functionality (Zhang et al., 2015). Thus, evaluating the effectiveness and practicality of HGF in the clinical management of Diabetes mellitus is essential (Fafalios et al., 2011). ...
Interactions and correlations between metabolites, pancreatic hormones, and growth factors. Note the gender differences, frequently opposite among metabolites, insulin and glucagon with growth factors, as well as the effect of metabolic disturbances induced by Diabetes type 2. The size of the arrows indicates the strength of the correlation and the direction whether the correlation was straight or inverse.
... Tumor cells showed discrete and overlapping expression of MET, Ecad and MITF (Supplementary Fig. 5d-f) and were co-expressed with NGFR in a small subset of tumor cells ( Supplementary Fig. 5 g, h). The investigation of BMCs (BMC1-M1) validated the cooccurrence of MET and NGFR expression in cellular subsets ( Supplementary Fig. 5i, j), suggesting that the MET tyrosine kinase receptor pathway may serve as a potent survival and maintenance mechanism in MBM and that the therapeutic targeting by small molecule inhibitors [77] may eliminate several tumor cell fractions including NGFR + cells potentially featuring resistance to BRAFi. ...
The development of brain metastases hallmarks disease progression in 20–40% of melanoma patients and is a serious obstacle to therapy. Understanding the processes involved in the development and maintenance of melanoma brain metastases (MBM) is critical for the discovery of novel therapeutic strategies. Here, we generated transcriptome and methylome profiles of MBM showing high or low abundance of infiltrated Iba1high tumor-associated microglia and macrophages (TAMs). Our survey identified potential prognostic markers of favorable disease course and response to immune checkpoint inhibitor (ICi) therapy, among them APBB1IP and the interferon-responsive gene ITGB7. In MBM with high ITGB7/APBB1IP levels, the accumulation of TAMs correlated significantly with the immune score. Signature-based deconvolution of MBM via single sample GSEA revealed enrichment of interferon-response and immune signatures and revealed inflammation, stress and MET receptor signaling. MET receptor phosphorylation/activation maybe elicited by inflammatory processes in brain metastatic melanoma cells via stroma cell-released HGF. We found phospho-METY1234/1235 in a subset of MBM and observed a marked response of brain metastasis-derived cell lines (BMCs) that lacked druggable BRAF mutations or developed resistance to BRAF inhibitors (BRAFi) in vivo to MET inhibitors PHA-665752 and ARQ197 (tivantinib). In summary, the activation of MET receptor in brain colonizing melanoma cells by stromal cell-released HGF may promote tumor self-maintenance and expansion and might counteract ICi therapy. Therefore, therapeutic targeting of MET possibly serves as a promising strategy to control intracranial progressive disease and improve patient survival.
... Mesenchymal epithelial transition (MET) encodes a receptor tyrosine kinase and that is activated by binding of its ligand, hepatocyte growth factor (HGF). 4 Dysregulation of the MET pathway involves amplification, fusion, overexpression, and mutation. 5 Several studies have indicated MET overexpression in 11%-43% of intrahepatic cholangiocarcinoma (IHCC) and 16%-80% in extrahepatic cholangiocarcinoma (EHCC). ...
Gallbladder cancer (GBC) is a highly invasive disease and the most prevalent malignancy of the biliary system. Patients with GBC are commonly diagnosed at a late stage and have an unfavorable prognosis. Palliative chemotherapy has been the standard care for recurrent or metastatic disease in the past decades. Recently, several targeted therapies have been investigated in advanced biliary tract cancer (BTC) including inhibitors of genes or pathways such as FGFR2 fusions or rearrangements, IDH1 mutations, and NTRK gene fusions. Also, several clinical studies involving molecular stratification have been performed in defined patient groups, for example, BRAF V600E and HER2. Mesenchymal epithelial transition(MET)encodes a tyrosine kinase receptor and its ligand hepatocyte growth factor is a proto-oncogene. Targeting the MET signaling pathway is an effective strategy in numerous cancer types. However, the poor efficacy of MET inhibitors has been demonstrated in several phase II studies, but currently no reports have explained the potential mechanisms of resistance to MET inhibitors in BTC. In this article, we report a case of metastatic GBC with MET amplification that exhibited a rapid response to crizotinib after the failure of two lines of chemotherapy. After the patient had progressed and discontinued crizotinib, cabozantinib was introduced. Analysis of circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) indicated a loss of MET amplification status. To our knowledge, this is the first case study demonstrating the use of NGS in ctDNA to monitor the development of acquired resistance during anti-MET treatment in GBC.
... In addition, This result coincides with result of Libetta,et al., (2013) who demonstrated that there is very significant increase of HGF levels in hemodialysis patients with low eGFR . Zhang, et al., (2015) showed that dialysis method act as stimulator to release HGF, like tumor necrosis factor and interleukin-1 (IL-1), which may play a role for HGF release . Moreover, the processes of dialysis may lead to the discharge of coagulation signals that change HGF from inactive to active structure. ...
Renal failure (RF) disease is one of the common clinical features of nephrology
patients and it represents a major and growing challenge for healthcare systems. The
prevalence rate of RF is increasing worldwide, primarily as a consequence of the
augmented incidence of diabetes, hypertension, and aging population .So, the present study
aimed to identify useful biomarkers correlating with most important processes that lead to
progression of RF and thus the study may contributes to therapeutic or diagnostic aspects.
The study has carried out in laboratories of the College of Science , Wasit University in
cooperation with Al-Zahraa Teaching Hospital , Al-Kut Teaching Hospital and Wasit
Center for Nephrology and Dialysis in Wasit Province , for the period extended from
November 2018 to October 2020. The study has included (100) patients (52 males and 48
females ). The age of these patients ranged <17 - >85 years old .The patients were
diagnosed according to renal failure criteria and confirmed as a renal failure cases by
specialized physicians and pathologists as well as their serum urea and creatinine levels that
were checked.. The control group consisted of 30 apparently healthy individuals (18) males
and (12) females who had no pathological state at the time of this study, all of them were
matched to patients, in age group and gender. Furthermore ,the current study was in
agreement with hospital ethics and approvals from all participants . The selected patients
were stratified according to the severity of RF into five stages based on estimate glomerular
filtration rate (eGFR) which determined mainly by testing for serum creatinine level .
... HGF/MET-targeted therapies have been introduced to the anticancer drug repertoire since 2011 with the approval of small molecule inhibitors such as crizotinib for treatment of NSCLC and cabozantinib for management of metastatic medullary thyroid cancer, renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC) and very recently capmatinib for management of NSCLC patients (Kazandjian et al., 2014;Viola et al., 2013;Dhillon, 2020). Multiple advanced clinical trials are currently testing the use of several small molecule MET tyrosine kinase inhibitors (TKIs) such as AMG 337, foretinib (GSK1363089), glesatinib (MGCD-265), golvatinib (E-7050), S49076, SAR125844, savolitinib (AZD6094, HMPL-504, volitinib), teponitinib (EMD-1,214,063) and tivantinib (ARQ-19) for treatment of various cancers, including lung, gastric, pancreatic, breast, cervical, prostate, head and neck cancers as well as gastroesophageal junction cancer (GEJ), CRC, HCC, RCC, GBM and cholangiocarcinoma among others ( Fig. 1) Moosavi et al., 2019;Zhang et al., 2015;Puccini et al., 2019). For instance, very recently the phase III of the SAVOIR trial found that savolitinib was associated with better outcome in MET-driven metastatic papillary renal cell carcinoma (PRCC) compared to sunitinib, which is the standard of care in these patients (Choueiri et al., 2020a). ...
MET receptor has emerged as a druggable target across several human cancers. Agents targeting MET and its ligand hepatocyte growth factor (HGF) including small molecules such as crizotinib, tivantinib and cabozantinib or antibodies including rilotumumab and onartuzumab have proven their values in different tumors. Recently, capmatinib was approved for treatment of metastatic lung cancer with MET exon 14 skipping. In this review, we critically examine the current evidence on how HGF/MET combination therapies may take advantage of synergistic effects, overcome primary or acquired drug resistance, target tumor microenvironment, modulate drug metabolism or tackle pharmacokinetic issues. Preclinical and clinical studies on the combination of HGF/MET-targeted agents with conventional chemotherapeutics or molecularly targeted treatments (EGFR, VEGFR, HER2, RAF/MEK, and PI3K/Akt targeting agents) and also the value of biomarkers are examined. Our deeper understanding of molecular mechanisms underlying successful pharmacological combinations is crucial to find the best personalized treatment regimens for cancer patients.
... Hepatocyte growth factor, a multifunctional cytokine, is involved in the signal transduction cascade of the HGF-c-met system, which can stimulate proliferation; dedifferentiation of various cell types; weaken cell-to-cell adhesion interactions; and promote the migration and invasion of tumor cells and the formation of tumor vessels. 11,12 Previous studies have shown that cyclin E and HGF are highly expressed in multiple malignant tumor types. [13][14][15][16] In the present study, the high expression of cyclin E and HGF was significantly associated with tumor size, differentiation degree, and TNM stage in patients with ESCC. ...
Cyclin E and hepatocyte growth factor (HGF) have been observed as a multifaceted factor in many cancers, and the assessment of microvascular density (MVD) and micro-lymphatic vessel density (MLVD) has been used to quantify tumor angiogenesis and lymphangiogenesis. The aim of this study was to explore the association between expression of cyclin E, HGF, MVD, and MLVD, and clinicopathologic parameters in esophageal squamous cell carcinoma (ESCC). The expression of cyclin E, HGF, MVD, and MLVD were detected using immunohistochemically anticyclin E, HGF, CD34, and lymphatic vessel endothelial hyaluronan receptor 1 in 168 surgically resected ESCC cases and 30 normal esophageal mucosal samples. The expression levels of cyclin E, HGF, MVD, and MLVD were higher compared to controls. High cyclin E and HGF expression was found more frequently in the tumors larger than 5 cm ( P < .001), with poorer differentiation ( P = .034) and higher tumor node metastasis (TNM) staging ( P = .009) compared to their counterparts. Both MVD and MLVD values were found to be higher in the tumors larger than 5 cm ( P < .001), with poorer differentiation ( P < .001) and higher TNM staging ( P < .001) compared to their counterparts. Furthermore, the expression of MVD and MLVD in both the high cyclin E and high HGF expression groups was significantly higher compared to the low cyclin E and HGF expression groups ( P < .001). This study demonstrated that high cyclin E and HGF expression is closely correlated with tumor size, tumor differentiation degree, and TNM stage in patients with ESCC. These findings proposed that cyclin E and HGF could serve as novel molecular markers for preoperational evaluation of ESCC.
... An association between HGF and EGF signaling has been established by Zhang et al. [40], where upon activation, these growth factors elicit the same cellular responses (Fig. 3). The binding of HGF or EGF to the respective receptors induces phosphorylation of PI3K which activates AKT, IkB kinase (IKK) and inhibits Caspase-9/BAD, thus mediating pro-apoptosis. ...
... Moreover, blocking the cMET receptor by cMET antagonists or cMET tyrosine kinase inhibitors (TKIs) represents alternative therapeutic strategies for modifying HGF-cMET signaling pathway [181,182]. HGF inhibitors can be used as single agents or in combination with other anticancer drugs such as cytostatic drugs or targeted compounds [182,183]. Most of the HGF-cMET inhibitors have shown encouraging results when used in drug combination studies. ...
... Given the results of those large studies targeting the MET pathway, further development of rilotumumab is not being pursued for patients with MET-positive gastric/GEJ adenocarcinoma or for the Japanese patient population. Other MET inhibitors are under investigation in the oncology setting as reviewed by Marano et al. and Zhang et al. (24,25); our data may be of relevance to these efforts. There were no noteworthy differences in the exposure of rilotumumab in this Japanese patient population compared with a Western patient population using the same doses of rilotumumab monotherapy (10 and 20 mg/kg Q2W), and pharmacokinetics were linear in the dose range tested (17). ...
Objective:
To evaluate the safety (including adverse events and dose-limiting toxicities [DLTs]), tolerability, pharmacokinetics and antitumor activity of the investigational MET inhibitor rilotumumab alone in patients with advanced solid tumors (Part 1) or in combination with cisplatin plus capecitabine (CX) in patients with MET-positive advanced gastric or gastroesophageal junction cancer (Part 2).
Methods:
Adult patients received 10 or 20 mg/kg intravenous (IV) rilotumumab every 2 weeks (Part 1) or 15 mg/kg IV rilotumumab every 3 weeks plus 80 mg/m2 cisplatin on Day 1 and 1000 mg/m2 capecitabine twice daily on Days 1-14 of every 21-day cycle (Part 2).
Results:
Nine patients enrolled in Part 1; 12 patients enrolled in Part 2. One DLT occurred (Grade 3 decreased appetite and stomatitis [Part 2]). Adverse events related to any treatment occurred in 17 patients (81%) and were Grade ≥3 in nine patients (43%). Rilotumumab pharmacokinetics appeared linear, and exposure was unaffected by CX. No patient who received rilotumumab monotherapy in Part 1 had a response. In Part 2, five of eight patients (63%) with measureable disease at baseline had a partial response and two patients (25%) had stable disease; median (95% CI) progression-free survival was 7.0 (2.4-15.4) months; overall survival was 18.2 (5.6-20.4) months.
Conclusions:
In combination with CX, rilotumumab appeared tolerable and showed antitumor activity in Japanese patients with MET-positive gastric/gastroesophageal junction cancer. However, owing to the results of recent Phase 3 trials of MET inhibitors (including rilotumumab), further development of rilotumumab in this setting is not being pursued. ClinicalTrials.gov Identifier: NCT01791374.
... MET regulates multiple cellular functions such as proliferation, survival and motility and displays low activity in normal cells. Aberrant MET activation in tumor cells promotes enhanced tumor cell growth, angiogenesis and invasion and is associated with poorer overall survival [8,15,16]. Oncogenic MET activation can result from various mechanisms including amplification of MET, elevated levels of its ligand, hepatocyte growth factor (HGF), mutations within the promoter region of HGF, constitutive kinase activity due to mutation and loss of negative regulatory mechanisms such as microRNAs [10,15,17,18]. Since the MET pathway is predominately activated in high-grade GBM cells, targeting MET could lead to selective killing of tumor cells whilst sparing normal cells for optimal anticancer therapy [15]. ...
... Aberrant MET activation in tumor cells promotes enhanced tumor cell growth, angiogenesis and invasion and is associated with poorer overall survival [8,15,16]. Oncogenic MET activation can result from various mechanisms including amplification of MET, elevated levels of its ligand, hepatocyte growth factor (HGF), mutations within the promoter region of HGF, constitutive kinase activity due to mutation and loss of negative regulatory mechanisms such as microRNAs [10,15,17,18]. Since the MET pathway is predominately activated in high-grade GBM cells, targeting MET could lead to selective killing of tumor cells whilst sparing normal cells for optimal anticancer therapy [15]. ...
... Oncogenic MET activation can result from various mechanisms including amplification of MET, elevated levels of its ligand, hepatocyte growth factor (HGF), mutations within the promoter region of HGF, constitutive kinase activity due to mutation and loss of negative regulatory mechanisms such as microRNAs [10,15,17,18]. Since the MET pathway is predominately activated in high-grade GBM cells, targeting MET could lead to selective killing of tumor cells whilst sparing normal cells for optimal anticancer therapy [15]. ...
Glioblastoma (GBM) is a lethal brain tumor with dismal prognosis. Current therapeutic options, consisting of surgery, chemotherapy and radiation, have only served to marginally increase patient survival. Receptor tyrosine kinases (RTKs) are dysregulated in approximately 90% of GBM; attributed to this, research has focused on inhibiting RTKs as a novel and effective therapy for GBM. Overexpression of RTK mesenchymal epithelial transition (MET), and its ligand, hepatocyte growth factor (HGF), in GBM highlights a promising new therapeutic target. This review will discuss the role of MET in cell cycle regulation, cell proliferation, evasion of apoptosis, cell migration and invasion, angiogenesis and therapeutic resistance in GBM. It will also discuss the modes of deregulation of HGF/MET and their regulation by microRNAs. As the HGF/MET pathway is a vital regulator of multiple pro-survival pathways, efforts and strategies for its exploitation for GBM therapy are also described.
