title: ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models.
abstract: EGFR blocking antibodies are approved for the treatment of colorectal cancer and head and neck squamous cell carcinoma (HNSCC). Although ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. To gain insight into these mechanisms, we generated potent blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955). We show that EGFR and ERBB3 are coactivated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits growth of these cell lines more effectively than blockade of either receptor alone. Blockade of EGFR with REGN955 strongly inhibited activation of ERK in HNSCC cell lines, whereas blockade of ERBB3 with REGN1400 strongly inhibited activation of Akt; only the combination of the 2 antibodies blocked both of these essential downstream pathways. We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth. Finally, although REGN1400 and REGN955 as single agents slowed the growth of HNSCC and colorectal cancer xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression. Our results indicate that activation of the Akt survival pathway by ERBB3/HER2 limits the effectiveness of EGFR inhibition, suggesting that REGN1400, which is currently in a phase I clinical trial, could provide benefit when combined with EGFR blocking antibodies.
authors.affiliation: Authors' Affiliation: Regeneron Pharmaceuticals, Inc., Tarrytown, New York.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.forename: Carla
authors.initials: C
authors.lastname: Castanaro
authors.forename: Bo
authors.initials: B
authors.lastname: Luan
authors.forename: Katie
authors.initials: K
authors.lastname: Yang
authors.forename: Liangfen
authors.initials: L
authors.lastname: Fan
authors.forename: Jeanette L
authors.initials: JL
authors.lastname: Fairhurst
authors.forename: Ashique
authors.initials: A
authors.lastname: Rafique
authors.forename: Terra B
authors.initials: TB
authors.lastname: Potocky
authors.forename: Jing
authors.initials: J
authors.lastname: Shan
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Delfino
authors.forename: Ergang
authors.initials: E
authors.lastname: Shi
authors.forename: Tammy
authors.initials: T
authors.lastname: Huang
authors.forename: Joel H
authors.initials: JH
authors.lastname: Martin
authors.forename: Gang
authors.initials: G
authors.lastname: Chen
authors.forename: Douglas
authors.initials: D
authors.lastname: Macdonald
authors.forename: John S
authors.initials: JS
authors.lastname: Rudge
authors.forename: Gavin
authors.initials: G
authors.lastname: Thurston
authors.forename: Christopher
authors.initials: C
authors.lastname: Daly
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051379:Mice; D011485:Protein Binding; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3