Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling

Hultberg, Anna; Morello, Virginia; Huyghe, Leander; Jonge, Natalie De; Blanchetot, Christophe; Hanssens, Valérie; Boeck, Gitte De; Silence, Karen; Festjens, Els; Heukers, Raimond; Roux, Benjamin; Lamballe, Fabienne; Ginestier, Christophe; Charafe-Jauffret, Emmanuelle; Maina, Flavio; Brouckaert, Peter; Saunders, Michael; Thibault, Alain; Dreier, Torsten; Haard, Hans de; Michieli, Paolo

doi:10.1158/0008-5472.can-15-0356

Cited by 34 publications

(46 citation statements)

References 43 publications

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“…42 ARGX-111 inhibits ligand-dependent cMET activation and shows cytotoxic activity in both cMET-expressing human cancer cells and patient-derived chronic lymphocytic leukemia and acute myeloid leukemia cells. In an orthotopic mouse model, ARGX-111 decreased the number of circulating tumor cells and suppressed metastasis.…”

Section: Anti-cmet Antibodiesmentioning

confidence: 99%

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

Kim

2017

Exp Mol Med

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Dysregulated receptor tyrosine kinase signaling in human cancer cells leads to tumor progression, invasion and metastasis. The receptor tyrosine kinase cMET is frequently overexpressed in cancer tissue, and activation of cMET signaling is related to drug resistance and the processes of carcinogenesis, invasion and metastasis. For that reason, cMET and its ligand, hepatocyte growth factor (HGF), are considered prime targets for the development of anticancer drugs. At least eight anti-cMET and four anti-HGF antibodies have been tested or are being tested in clinical trials. However, to date none of these HGF/cMET inhibitors have shown significant efficacy in clinical trials. Furthermore, no receptor tyrosine kinase inhibitors primarily targeting cMET have been approved. Given that neutralization of HGF or cMET does not cause significant adverse effects, inhibition of the HGF/cMET signaling pathway appears to be safe. In this review, we summarized the completed and ongoing clinical trials testing antibody- or protein-based anticancer drugs targeting cMET and HGF.

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Section: Anti-cmet Antibodiesmentioning

confidence: 99%

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

Kim

2017

Exp Mol Med

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“…Drug resistance remains a vexing problem in the treatment of cancer patients. The aberrant activation of HGF and its receptor MET has been strongly implicated in the malignant transformation and progression of several tumours 8,24 and is frequently implicated in resistance to targeted therapies 25,26 . Feng et al found that significantly greater frequencies of high HGF and MET receptor expression were observed in ALK-positive NSCLC patients 10 .…”

Section: Discussionmentioning

confidence: 99%

Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

et al. 2020

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Alectinib is a second-generation anaplastic lymphoma kinase (ALK) inhibitor that has sufficient clinical efficacy and satisfactory safety in ALK-positive non-small cell lung cancer (NSCLC) patients with or without brain metastasis. Alectinib has now become an important drug in the first-line treatment of advanced ALK-positive NSCLC; however, resistance is almost inevitable. The increased expression of hepatocyte growth factor (HGF) and its physiological receptor tyrosine kinase MET have been shown to be linked to acquired resistance to various tyrosine kinase inhibitors (TKIs), and this phenomenon has been observed in some ALK-positive NSCLC tumour tissues. In this study, we found that HGF levels in the culture supernatant of an ALK-positive cell line tended to increase with time and could be further increased by alectinib in a time-dependent manner. Exogenous or endogenous HGF did not cause resistance to the ALK/MET double-targeted small molecule inhibitor crizotinib, but it was an important cause of alectinib resistance. Furthermore, Gab1 was a key effector in the HGF/MET signal transduction pathway that mediated alectinib resistance. The antidiabetic drug metformin combined with alectinib overcame alectinib resistance triggered by HGF/ MET through disrupting the complex between MET and Gab1, thereby inhibiting Gab1 phosphorylation and the activation of downstream signal transduction pathways. These results suggest that metformin combined with alectinib may be useful for overcoming alectinib resistance induced by the activation of the HGF/MET signalling pathway and improving the efficacy of alectinib.

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“…Empirical evaluations of these molecules using the aforementioned criteria was needed to identify the best pair of anti-EGFR and anti-c-Met Abs to be put into the JNJ-61186372 BsAb design. A recent report of an antagonistic anti-Met antibody with Fc engineering has been described to have enhanced ADCC activity 50 . This antibody outperformed an ADCC-dead version of the antibody that could still inhibit c-Met signaling in multiple mouse models 50 …”

Section: Discussionmentioning

confidence: 99%

Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells

Grugan

Dorn

Jarantow

et al. 2016

mAbs

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Epidermal growth factor receptor (EGFR) mutant non-small cell lung cancers acquire resistance to EGFR tyrosine kinase inhibitors through multiple mechanisms including c-Met receptor pathway activation. We generated a bispecific antibody targeting EGFR and c-Met (JNJ-61186372) demonstrating anti-tumor activity in wild-type and mutant EGFR settings with c-Met pathway activation. JNJ-61186372 was engineered with low fucosylation (<10 %), resulting in enhanced antibody-dependent cell-mediated cytotoxicity and FcγRIIIa binding. In vitro and in vivo studies with the single-arm EGFR or c-Met versions of JNJ-61186372 identified that the Fc-activity of JNJ-61186372 is mediated by binding of the anti-EGFR arm and required for inhibition of EGFR-driven tumor cells. In a tumor model driven by both EGFR and c-Met, treatment with Fc-silent JNJ-61186372 or with c-Met single-arm antibody reduced tumor growth inhibition compared to treatment with JNJ-61186372, suggesting that the Fc function of JNJ-61186372 is essential for maximal tumor inhibition. Moreover in this same model, downregulation of both EGFR and c-Met receptors was observed upon treatment with Fc-competent JNJ-61186372, suggesting that the Fc interactions are necessary for down-modulation of the receptors in vivo and for efficacy. These Fc-mediated activities, in combination with inhibition of both the EGFR and c-Met signaling pathways, highlight the multiple mechanisms by which JNJ-61186372 combats therapeutic resistance in EGFR mutant patients.

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Depleting MET-Expressing Tumor Cells by ADCC Provides a Therapeutic Advantage over Inhibiting HGF/MET Signaling

Cited by 34 publications

References 43 publications

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

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

Metformin reduces HGF-induced resistance to alectinib via the inhibition of Gab1

Fc-mediated activity of EGFR x c-Met bispecific antibody JNJ-61186372 enhanced killing of lung cancer cells

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