A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity

Castoldi, Raffaella; Ecker, Veronika; Wiehle, Laura; Majety, Meher; Busl-Schuller, R; Asmussen, M; Nopora, Adam; Jucknischke, Ute; Osl, Franz; Kobold, Sebastian; Scheuer, Werner; Venturi, Miro; Klein, Christian; Niederfellner, Gerhard; Sustmann, Claudio

doi:10.1038/onc.2013.245

Cited by 54 publications

(41 citation statements)

References 47 publications

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“…Previous studies have shown that HGF sustains resistance against EGFR inhibition in cell lines (44,45). We now suggest that concomitant inhibition of the two targets-MET and EGFR-hits CCICs that feature defined genetic traits such as wild-type RAS pathway genes.…”

Section: Discussionmentioning

confidence: 60%

MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors

et al. 2014

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Metastatic colorectal cancer remains largely incurable, although in a subset of patients, survival is prolonged by new targeting agents such as anti-EGF receptor (anti-EGFR) antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer-initiating cell (CCIC), which may also confer therapeutic resistance. However, how CCICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CCICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed "xenospheres," were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CCICs. Xenosphere CCICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts; like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, whereas those harboring wild-type RAS pathway genes (RAS wt ) were sensitive. Notably, the effects of EGFR inhibition in sensitive CCICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found that the MET receptor ligand hepatocyte growth factor (HGF) was especially active in supporting in vitro CCIC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CCIC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RAS wt CCICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof-of-concept for concurrent targeting of these two pathways in the clinical setting. Cancer Res; 74(6); 1857-69. Ó2014 AACR.

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Section: Discussionmentioning

confidence: 60%

MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors

et al. 2014

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“…In other various tumor entities, resistance against EGFR inhibition or resistance against anti-VEGF therapy has been demonstrated to be mediated by compensatory upregulation of phosphorylated c-Met as an alternative signaling pathway. Inhibition of c-Met has been discussed as a potential target in combination therapies in order to overcome a c-Met-induced escape from EGFR inhibition [50,51,52,53,54,55,56] or escape from anti-VEGF therapy [31,57,58,59,60], as has been demonstrated in various tumor entities. These mechanisms have also been discussed for neuroendocrine tumors [19,20,21,31,61].…”

Section: Discussionmentioning

confidence: 99%

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for ‘Off-Target' Effects Not Mediated by c-Met Inhibition

et al. 2015

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Background/Aims: The hepatocyte growth factor/transmembrane tyrosine kinase receptor c-Met has been defined as a potential target in antitumoral treatment of various carcinomas. We aimed to investigate the direct effect of c-Met inhibition on neuroendocrine tumor cells in vitro. Methods: The effects of the multi-tyrosine kinase inhibitors cabozantinib and tivantinib and of the highly specific c-Met inhibitor INC280 were investigated in human pancreatic neuroendocrine BON1, bronchopulmonary NCI-H727 and midgut GOT1 cells in vitro. Results: INC280, cabozantinib and tivantinib inhibited c-Met phosphorylation, respectively. However, while equimolar concentrations (10 μM) of cabozantinib and tivantinib inhibited cell viability and cell migration, INC280 had no inhibitory effect. Knockdown experiments with c-Met siRNA also did not demonstrate effects on cell viability. Cabozantinib and tivantinib caused a G2 arrest in neuroendocrine tumor cells. Conclusions: Our in vitro data suggest that c-Met inhibition alone is not sufficient to exert direct antitumoral or antimigratory effects in neuroendocrine tumor cells. The multi-tyrosine kinase inhibitors cabozantinib and tivantinib show promising antitumoral and antimigratory effects in neuroendocrine tumor cells, which are most probably ‘off-target' effects, not mediated by c-Met.

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“…This bispecific antibody was also shown to be 7-fold more potent in inhibiting migration than a combination of cetuximab and 5D5.v2 at low concentrations. Furthermore, MetHer1 down regulated EGFR and c-Met downstream signaling proteins, such as p-ERK and p-Akt, in five cancer cell lines in vitro, and inhibited tumor growth in NSCLC xenografts in vivo [63].…”

Section: Egfr/c-met Inhibitor Pre-clinical Studiesmentioning

confidence: 95%

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

Stone¹,

Harrington²,

Frakes³

et al. 2014

J Carcinog & Mutagen

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EGFR and c-Met are receptor tyrosine kinases that are implicated in tumor development and progression in several types of cancer. Both EGFR and c-Met, which are known to be overexpressed and mutated in cancer, share common signaling pathways, including the PI3K/ Akt and MAPK pathways. Small molecule tyrosine kinase inhibitors and monoclonal antibodies that work against EGFR and c-Met are at the forefront of cancer therapy, but their individual efficacies are limited due to the development of drug resistance. In recent pre-clinical studies, we observed that combination therapy using mTOR and Wnt inhibitors with EGFR or c-Met tyrosine kinase inhibitors resulted in overcoming drug resistance. Our studies also indicated that EGFR and c-Met tyrosine kinase inhibitor resistance may be due to activation of alternative signaling pathways. The development of additional combinatorial therapies is underway, and various combinations of inhibitors have shown promising results in clinical trials. Future studies in this direction could be the basis for development of new cancer therapeutics, utilizing EGFR and c-Met inhibitors, which could greatly improve patient prognosis.

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A novel bispecific EGFR/Met antibody blocks tumor-promoting phenotypic effects induced by resistance to EGFR inhibition and has potent antitumor activity

Cited by 54 publications

References 47 publications

MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors

MET Signaling in Colon Cancer Stem-like Cells Blunts the Therapeutic Response to EGFR Inhibitors

Cabozantinib and Tivantinib, but Not INC280, Induce Antiproliferative and Antimigratory Effects in Human Neuroendocrine Tumor Cells in vitro: Evidence for ‘Off-Target' Effects Not Mediated by c-Met Inhibition

EGFR and c-Met Inhibitors are Effective in Reducing Tumorigenicity in Cancer

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