The HGF/MET Signaling and Therapeutics in Cancer

Thewke, Douglas P.; Kou, Jianqun; Fulmer, Makenzie; Xie, Qian

doi:10.1007/978-981-10-7296-3_8

Cited by 5 publications

(3 citation statements)

References 206 publications

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“…In addition to proliferation and angiogenesis, MET activation is known to promote cancer invasion and metastasis [ 3 , 40 ]. Thus, it is worthwhile to determine whether INC280 prevents MHCC97H metastasis at similar level as it inhibits cell proliferation in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…Aberrant activation of MET signaling is significantly correlated with cancer malignancy and poor clinical outcomes [ 1 – 3 ]. While overexpression of hepatocyte growth factor (HGF) by stromal or tumor cells may result in ligand-dependent MET activation in a paracrine or autocrine manner [ 4 , 5 ], focal amplification of the MET receptor gene (MET amp ) [ 6 , 7 ], its point mutation (MET mut ) [ 8 , 9 ], or alternative splicing of its mRNA [ 10 , 11 ] also may cause a ligand-independent MET activation.…”

Section: Introductionmentioning

confidence: 99%

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Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody

et al. 2018

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BackgroundAberrant MET tyrosine kinase signaling is known to cause cancer initiation and progression. While MET inhibitors are in clinical trials against several cancer types, the clinical efficacies are controversial and the molecular mechanisms toward sensitivity remain elusive.MethodsWith the goal to investigate the molecular basis of MET amplification (METamp) and hepatocyte growth factor (HGF) autocrine-driven tumors in response to MET tyrosine kinase inhibitors (TKI) and neutralizing antibodies, we compared cancer cells harboring METamp (MKN45 and MHCCH97H) or HGF-autocrine (JHH5 and U87) for their sensitivity and downstream biological responses to a MET-TKI (INC280) and an anti-MET monoclonal antibody (MetMab) in vitro, and for tumor inhibition in vivo.ResultsWe find that cancer cells driven by METamp are more sensitive to INC280 than are those driven by HGF-autocrine activation. In METamp cells, INC280 induced a DNA damage response with activation of repair through the p53BP1/ATM signaling pathway. Although MetMab failed to inhibit METamp cell proliferation and tumor growth, both INC280 and MetMab reduced HGF-autocrine tumor growth. In addition, we also show that HGF stimulation promoted human HUVEC cell tube formation via the Src pathway, which was inhibited by either INC280 or MetMab. These observations suggest that in HGF-autocrine tumors, the endothelial cells are the secondary targets MET inhibitors.ConclusionsOur results demonstrate that METamp and HGF-autocrine activation favor different molecular mechanisms. While combining MET TKIs and ATM inhibitors may enhance the efficacy for treating tumors harboring METamp, a combined inhibition of MET and angiogenesis pathways may improve the therapeutic efficacy against HGF-autocrine tumors.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1628-y) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody

et al. 2018

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“…Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality due to lacking effective therapeutics [ 1 ]. While hepatitis B or C virus (HBV/HCV) infection is a major cause of HCC, aberrant activation of c-Met oncogene, the receptor of hepatocyte growth factor (HGF), plays an important role in HCC initiation and progression [ 2 , 3 ]. Experimentally, overproduction of the HBV L envelope protein leads to the formation of HBV surface antigen particles that accumulate in high concentrations in hepatocytes and ultimately induce carcinogenesis [ 4 ].…”

Section: Introductionmentioning

confidence: 99%

Tyrosine kinase signaling-independent MET-targeting with CAR-T cells

Qin,

Lee

et al. 2023

J Transl Med

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Background Recent progress in cancer immunotherapy encourages the expansion of chimeric antigen receptor (CAR) T cell therapy in solid tumors including hepatocellular carcinoma (HCC). Overexpression of MET receptor tyrosine kinase is common in HCC; however, MET inhibitors are effective only when MET is in an active form, making patient stratification difficult. Specific MET-targeting CAR-T cells hold the promise of targeting HCC with MET overexpression regardless of signaling pathway activity. Methods MET-specific CARs with CD28ζ or 4-1BBζ as co-stimulation domains were constructed. MET-CAR-T cells derived from healthy subjects (HS) and HCC patients were evaluated for their killing activity and cytokine release against HCC cells with various MET activations in vitro, and for their tumor growth inhibition in orthotopic xenograft models in vivo. Results MET-CAR.CD28ζ and MET-CAR.4-1BBζ T cells derived from both HS and HCC patients specifically killed MET-positive HCC cells. When stimulated with MET-positive HCC cells in vitro, MET-CAR.CD28ζ T cells demonstrated a higher level of cytokine release and expression of programmed cell death protein 1 (PD-1) than MET-CAR.4-1BBζ T cells. When analyzed in vivo, MET-CAR.CD28ζ T cells more effectively inhibited HCC orthotopic tumor growth in mice when compared to MET-CAR.4-1BBζ T cells. Conclusion We generated and characterized MET-specific CAR-T cells for targeting HCC with MET overexpression regardless of MET activation. Compared with MET-CAR.4-1BBζ, MET-CAR.CD28ζ T cells showed a higher anti-HCC potency but also a higher level of T cell exhaustion. While MET-CAR.CD28ζ is preferred for further development, overcoming the exhaustion of MET-CAR-T cells is necessary to improve their therapeutic efficacy in vivo.

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3D-QSAR-aided design of potent c-Met inhibitors using molecular dynamics simulation and binding free energy calculation

Balasubramanian

Balupuri

Bhujbal

et al. 2018

Journal of Biomolecular Structure and Dynamics

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Mesenchymal-epithelial transition factor (c-Met) is a member of receptor tyrosine kinase. It involves in various cellular signaling pathways which includes proliferation, motility, migration, and invasion. Over-expression of c-Met has been reported in various cancers. Hence, it is an ideal therapeutic target for cancer. The main objective of the study is to identify crucial residues involved in the inhibition of c-Met kinase and to design a series of potent imidazo [4,5-b] pyrazine derivatives as c-Met inhibitors. Docking was used to identify important active site residues involved in the inhibition of c-Met kinase which was further validated by 100 ns of molecular dynamics simulation and free energy calculation using molecular mechanics generalized born surface area. Furthermore, binding energy decomposition identified that residues Tyr1230, Met1211, Asp1222, Tyr1159, Met1160, Val1092, Ala1108, and Leu1157 contributed favorably to the binding stability of compound 32. Receptor-guided Comparative Molecular Field Analysis (CoMFA) (q = 0.751, NOC = 6, r = 0.933) and Comparative Molecular Similarity Indices Analysis (COMSIA) (q = 0.744, NOC = 6, r = 0.950) models were generated based on the docked conformation of the most active compound 32. The robustness of these models was tested using various validation techniques and found to be predictive. The results of CoMFA and CoMSIA contour maps exposed the regions favorable to enhance the activity. Based on this information, 27 novel c-Met inhibitors were designed. These designed compounds exhibited potent activity than the most active compound of the existing dataset. Communicated by Ramaswamy H. Sarma.

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The HGF/MET Signaling and Therapeutics in Cancer

Cited by 5 publications

References 206 publications

Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody

Differential responses of MET activations to MET kinase inhibitor and neutralizing antibody

Tyrosine kinase signaling-independent MET-targeting with CAR-T cells

3D-QSAR-aided design of potent c-Met inhibitors using molecular dynamics simulation and binding free energy calculation

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