title: Dual targeting of EGFR and HER3 with MEHD7945A overcomes acquired resistance to EGFR inhibitors and radiation.
abstract: EGF receptor (EGFR) inhibition is efficacious in cancer therapy, but initially sensitive tumors often develop resistance. In this study, we investigated the potential to overcome acquired resistance to EGFR inhibitors with MEHD7945A, a monoclonal antibody that dually targets EGFR and HER3 (ErbB3). In cancer cells resistant to cetuximab and erlotinib, we found that MEHD7945A, but not single target EGFR inhibitors, could inhibit tumor growth and cell-cycle progression in parallel with EGFR/HER3 signaling pathway modulation. MEHD7945A was more effective than a combination of cetuximab and anti-HER3 antibody at inhibiting both EGFR/HER3 signaling and tumor growth. In human tumor xenograft models, we confirmed the greater antitumor potency of MEHD7945A than cetuximab or erlotinib. MEHD7945A retained potent activity in tumors refractory to EGFR inhibitor alone. Furthermore, MEHD7945A also limited cross-resistance to radiation in EGFR inhibitor-resistant cells by modulating cell-cycle progression and repair processes that control apoptotic cell death. Taken together, our findings confirm an important role of compensatory HER3 signaling in the development of acquired resistance to EGFR inhibitors and offer preclinical proof-of-concept that MEHD7945A can effectively overcome EGFR inhibitor resistance.
authors.affiliation: Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53792, USA.
authors.forename: Shyhmin
authors.initials: S
authors.lastname: Huang
authors.forename: Chunrong
authors.initials: C
authors.lastname: Li
authors.forename: Eric A
authors.initials: EA
authors.lastname: Armstrong
authors.forename: Chimera R
authors.initials: CR
authors.lastname: Peet
authors.forename: Jarob
authors.initials: J
authors.lastname: Saker
authors.forename: Lukas C
authors.initials: LC
authors.lastname: Amler
authors.forename: Mark X
authors.initials: MX
authors.lastname: Sliwkowski
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000532:radiotherapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D006258:Head and Neck Neoplasms / Q000188:drug therapy*; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000532:radiotherapy; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D007074:Immunoglobulin G; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C569960:MEHD7945A