PMID- 26879245 OWN - NLM STAT- MEDLINE DCOM- 20161012 LR - 20211203 IS - 1471-2407 (Electronic) IS - 1471-2407 (Linking) VI - 16 DP - 2016 Feb 16 TI - Anti-c-Met monoclonal antibody ABT-700 breaks oncogene addiction in tumors with MET amplification. PG - 105 LID - 10.1186/s12885-016-2138-z [doi] LID - 105 AB - BACKGROUND: c-Met is the receptor tyrosine kinase for hepatocyte growth factor (HGF) encoded by the MET proto-oncogene. Aberrant activation of c-Met resulting from MET amplification and c-Met overexpression is associated with poor clinical outcome in multiple malignancies underscoring the importance of c-Met signaling in cancer progression. Several c-Met inhibitors have advanced to the clinic; however, the development of inhibitory c-Met-directed therapeutic antibodies has been hampered by inherent agonistic activity. METHOD: We generated and tested a bivalent anti-c-Met monoclonal antibody ABT-700 in vitro for binding potency and antagonistic activity and in vivo for antitumor efficacy in human tumor xenografts. Human cancer cell lines and gastric cancer tissue microarrays were examined for MET amplification by fluorescence in situ hybridization (FISH). RESULTS: ABT-700 exhibits a distinctive ability to block both HGF-independent constitutive c-Met signaling and HGF-dependent activation of c-Met. Cancer cells addicted to the constitutively activated c-Met signaling driven by MET amplification undergo apoptosis upon exposure to ABT-700. ABT-700 induces tumor regression and tumor growth delay in preclinical tumor models of gastric and lung cancers harboring amplified MET. ABT-700 in combination with chemotherapeutics also shows additive antitumor effect. Amplification of MET in human cancer tissues can be identified by FISH. CONCLUSIONS: The preclinical attributes of ABT-700 in blocking c-Met signaling, inducing apoptosis and suppressing tumor growth in cancers with amplified MET provide rationale for examining its potential clinical utility for the treatment of cancers harboring MET amplification. FAU - Wang, Jieyi AU - Wang J AD - AbbVie, North Chicago, IL, USA. jieyi.wang@abbvie.com. AD - AbbVie Biotherapeutics, 1500 Seaport Blvd., Redwood City, CA, 94063, USA. jieyi.wang@abbvie.com. FAU - Goetsch, Liliane AU - Goetsch L AD - IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoleon III, F-74164, Saint-Julien-en-Genevois, France. liliane.Goetsch@pierre-fabre.com. FAU - Tucker, Lora AU - Tucker L AD - AbbVie, North Chicago, IL, USA. lora.tucker@abbvie.com. FAU - Zhang, Qian AU - Zhang Q AD - AbbVie, North Chicago, IL, USA. cindy.zhang@abbvie.com. FAU - Gonzalez, Alexandra AU - Gonzalez A AD - IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoleon III, F-74164, Saint-Julien-en-Genevois, France. alexandra.gonzalez@pierre-fabre.com. FAU - Vaidya, Kedar S AU - Vaidya KS AD - AbbVie, North Chicago, IL, USA. kedar.vaidya@abbvie.com. FAU - Oleksijew, Anatol AU - Oleksijew A AD - AbbVie, North Chicago, IL, USA. andy.oleksijew@abbvie.com. FAU - Boghaert, Erwin AU - Boghaert E AD - AbbVie, North Chicago, IL, USA. Erwin.Boghaert@abbvie.com. FAU - Song, Minghao AU - Song M AD - Abbott Molecular, Des Plaines, IL, USA. Minghao.song@abbott.com. FAU - Sokolova, Irina AU - Sokolova I AD - Abbott Molecular, Des Plaines, IL, USA. irina.sokolova@abbott.com. FAU - Pestova, Ekaterina AU - Pestova E AD - Abbott Molecular, Des Plaines, IL, USA. ekaterina.pestova@abbott.com. FAU - Anderson, Mark AU - Anderson M AD - AbbVie, North Chicago, IL, USA. mark.g.anderson@abbvie.com. FAU - Pappano, William N AU - Pappano WN AD - AbbVie, North Chicago, IL, USA. bill.pappano@abbvie.com. FAU - Ansell, Peter AU - Ansell P AD - AbbVie, North Chicago, IL, USA. peter.ansell@abbvie.com. FAU - Bhathena, Anahita AU - Bhathena A AD - AbbVie, North Chicago, IL, USA. anahita.bhathena@abbvie.com. FAU - Naumovski, Louie AU - Naumovski L AD - AbbVie Biotherapeutics, 1500 Seaport Blvd., Redwood City, CA, 94063, USA. louie.naumovski@abbvie.com. FAU - Corvaia, Nathalie AU - Corvaia N AD - IRPF, Centre d'Immunologie Pierre Fabre 5, Av Napoleon III, F-74164, Saint-Julien-en-Genevois, France. nathalie.corvaia@pierre-fabre.com. FAU - Reilly, Edward B AU - Reilly EB AD - AbbVie, North Chicago, IL, USA. ed.reilly@abbvie.com. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160216 PL - England TA - BMC Cancer JT - BMC cancer JID - 100967800 RN - 0 (Antibodies, Monoclonal) RN - 0 (Antineoplastic Agents) RN - 0 (MAS1 protein, human) RN - 0 (Proto-Oncogene Mas) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-met) SB - IM MH - Animals MH - Antibodies, Monoclonal/metabolism/*pharmacology/therapeutic use MH - Antineoplastic Agents/metabolism/*pharmacology/therapeutic use MH - Cell Line, Tumor MH - Gene Amplification MH - Humans MH - Male MH - Mice MH - Mice, SCID MH - Neoplasms, Experimental/drug therapy/genetics/metabolism/pathology MH - Protein Binding MH - Proto-Oncogene Mas MH - Proto-Oncogene Proteins c-met/antagonists & inhibitors/*drug effects/*genetics MH - Xenograft Model Antitumor Assays PMC - PMC4755020 EDAT- 2016/02/18 06:00 MHDA- 2016/10/13 06:00 PMCR- 2016/02/16 CRDT- 2016/02/17 06:00 PHST- 2015/10/29 00:00 [received] PHST- 2016/02/08 00:00 [accepted] PHST- 2016/02/17 06:00 [entrez] PHST- 2016/02/18 06:00 [pubmed] PHST- 2016/10/13 06:00 [medline] PHST- 2016/02/16 00:00 [pmc-release] AID - 10.1186/s12885-016-2138-z [pii] AID - 2138 [pii] AID - 10.1186/s12885-016-2138-z [doi] PST - epublish SO - BMC Cancer. 2016 Feb 16;16:105. doi: 10.1186/s12885-016-2138-z.