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

Kim, Ki‐Hyun; Kim, Hyori

doi:10.1038/emm.2017.17

Cited by 68 publications

(65 citation statements)

References 71 publications

(51 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Targeting the HGF-c-MET pathway has been approached for the treatment of a variety of solid tumours with deregulated c-MET 44. However, tyrosine kinase inhibitors (TKI) of c-MET, monoclonal antibodies or small molecules designed to block the HGF/c-MET interaction have proven insufficient 45.…”

Section: Discussionmentioning

confidence: 99%

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Luna

Boni

Cuatrecasas

et al. 2018

Gut

View full text Add to dashboard Cite

Background and aimsPancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumour with a poor prognosis using current treatments. Targeted therapies may offer a new avenue for more effective strategies. Dual-specificity tyrosine regulated kinase 1A (DYRK1A) is a pleiotropic kinase with contradictory roles in different tumours that is uncharacterised in PDAC. Here, we aimed to investigate the role of DYRK1A in pancreatic tumorigenesis.DesignWe analysed DYRK1A expression in PDAC genetic mouse models and in patient samples. DYRK1A function was assessed with knockdown experiments in pancreatic tumour cell lines and in PDAC mouse models with genetic reduction of Dyrk1a dosage. Furthermore, we explored a mechanistic model for DYRK1A activity.ResultsWe showed that DYRK1A was highly expressed in PDAC, and that its protein level positively correlated with that of c-MET. Inhibition of DYRK1A reduced tumour progression by limiting tumour cell proliferation. DYRK1A stabilised the c-MET receptor through SPRY2, leading to prolonged activation of extracellular signal-regulated kinase signalling.ConclusionsThese findings reveal that DYRK1A contributes to tumour growth in PDAC, at least through regulation of c-MET accumulation, suggesting that inhibition of DYRK1A could represent a novel therapeutic target for PDAC.

show abstract

Section: Discussionmentioning

confidence: 99%

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Luna

Boni

Cuatrecasas

et al. 2018

Gut

View full text Add to dashboard Cite

show abstract

“…Their potential immunogenicity and high production costs are of particular concern for this modality. In addition, selective c‐met small‐molecule inhibitors have failed to gain approval due to adverse effects, dose‐limiting toxicities or acquired resistance; therefore, novel approaches that suppress HGF/c‐met signaling are needed . In the last decade, aptamers have emerged as attractive alternatives to antibodies and small molecules and have found use in diagnostic, therapeutic, imaging and targeting applications .…”

Section: Discussionmentioning

confidence: 99%

“…5 We evaluated the mRNA expression of c-met in two independent publicly available data sets and showed that c-met While multiple antibodies that target c-met or HGF are under preclinical and clinical development, none of them have shown significant clinical benefit to patients. 29 Their potential immunogenicity and high production costs are of particular concern for this modality.…”

Section: Discussionmentioning

confidence: 99%

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

Zhang

Gao

Zhou

et al. 2018

J Cellular Molecular Medi

View full text Add to dashboard Cite

Hepatocyte growth factor (HGF)/c‐met pathway activation has been implicated in the pathogenesis of multiple myeloma (MM), and blocking this pathway has been considered a rational therapeutic strategy for treating MM. Aptamers are single‐stranded nucleic acid molecules that fold into complex 3D structures and bind to a variety of targets. Recently, it was reported that DNA aptamer SL1 exhibited high specificity and affinity for c‐met and inhibited HGF/c‐met signaling in SNU‐5 cells. However, as the first c‐met‐targeted DNA aptamer to be identified, application of SL1 to myeloma treatment requires further investigation. Here, we explore the potential application of SL1 in MM. Our results indicated that c‐met expression is gradually increased in MM patients and contributes to poor outcomes. SL1 selectively bound to c‐met‐positive MM cells but not to normal B cells and suppressed the growth, migration and adhesion of MM cells in vitro in a co‐culture model performed with HS5 cells, wherein SL1 inhibited HGF‐induced activation of c‐met signaling. In vivo and ex vivo fluorescence imaging showed that SL1 accumulated in the c‐met positive tumour areas. In addition, SL1 was active against CD138+ primary MM cells and displayed a synergistic inhibition effect with bortezomib. Collectively, our data suggested that SL1 could be beneficial as a c‐met targeted antagonist in MM.

show abstract

“…Recombinant protein (truncated HGF, decoy c-Met) was not successful in clinical trials due to several factors, including short half-life and low target affinity limiting the intended efficacy [28]. Several HGF-neutralizing antibodies have been developed with two currently active in clinical trials [29]. However, the inhibitory targeting of c-Met by an antibody has been difficult since the bivalency of antibodies often induces receptor dimerization, which potentially causes cancer cell proliferation and migration.…”

Section: Discussionmentioning

confidence: 99%

Machine Learning-Guided Prediction of Antigen-Reactive In Silico Clonotypes Based on Changes in Clonal Abundance through Bio-Panning

Yoo

Lee

Jung³

et al. 2020

Biomolecules

View full text Add to dashboard Cite

c-Met is a promising target in cancer therapy for its intrinsic oncogenic properties. However, there are currently no c-Met-specific inhibitors available in the clinic. Antibodies blocking the interaction with its only known ligand, hepatocyte growth factor, and/or inducing receptor internalization have been clinically tested. To explore other therapeutic antibody mechanisms like Fc-mediated effector function, bispecific T cell engagement, and chimeric antigen T cell receptors, a diverse panel of antibodies is essential. We prepared a chicken immune scFv library, performed four rounds of bio-panning, obtained 641 clones using a high-throughput clonal retrieval system (TrueRepertoireTM, TR), and found 149 antigen-reactive scFv clones. We also prepared phagemid DNA before the start of bio-panning (round 0) and, after each round of bio-panning (round 1–4), performed next-generation sequencing of these five sets of phagemid DNA, and identified 860,207 HCDR3 clonotypes and 443,292 LCDR3 clonotypes along with their clonal abundance data. We then established a TR data set consisting of antigen reactivity for scFv clones found in TR analysis and the clonal abundance of their HCDR3 and LCDR3 clonotypes in five sets of phagemid DNA. Using the TR data set, a random forest machine learning algorithm was trained to predict the binding properties of in silico HCDR3 and LCDR3 clonotypes. Subsequently, we synthesized 40 HCDR3 and 40 LCDR3 clonotypes predicted to be antigen reactive (AR) and constructed a phage-displayed scFv library called the AR library. In parallel, we also prepared an antigen non-reactive (NR) library using 10 HCDR3 and 10 LCDR3 clonotypes predicted to be NR. After a single round of bio-panning, we screened 96 randomly-selected phage clones from the AR library and found out 14 AR scFv clones consisting of 5 HCDR3 and 11 LCDR3 AR clonotypes. We also screened 96 randomly-selected phage clones from the NR library, but did not identify any AR clones. In summary, machine learning algorithms can provide a method for identifying AR antibodies, which allows for the characterization of diverse antibody libraries inaccessible by traditional methods.

show abstract

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

Cited by 68 publications

References 71 publications

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth

Targeting c‐met receptor tyrosine kinase by the DNA aptamer SL1 as a potential novel therapeutic option for myeloma

Machine Learning-Guided Prediction of Antigen-Reactive In Silico Clonotypes Based on Changes in Clonal Abundance through Bio-Panning

Contact Info

Product

Resources

About