title: Insulin-like growth factor 1 receptor mediated tyrosine 845 phosphorylation of epidermal growth factor receptor in the presence of monoclonal antibody cetuximab.
abstract: The epidermal growth factor receptor (EGFR) is frequently overexpressed in head and neck squamous cell carcinoma (HNSCC) and several other human cancers. Monoclonal antibodies, such as cetuximab that block EGFR signaling, have emerged as valuable molecular targeting agents in clinical cancer therapy. Prolonged exposure to cetuximab can result in cells acquiring resistance by a process that remains incompletely understood.
  
  
  
  In this study, we analyzed the immediate early molecular response of cetuximab on physical interactions between EGFR and Insulin growth factor 1 like receptor (IGF-1R) in head and neck cancer cells that are resistant to cetuximab. Co-immunoprecipitation, small molecule inhibitors against phospho-Src and IGF-1R, quantitative western blot of EGFR and Src phosphorylation, cell proliferation assays were used to suggest the role of IGF-1R mediated phosphorylation of specific tyrosine Y845 on EGFR via increased heterodimerization of EGFR and IGF-1R in cetuximab resistant cells.
  
  
  
  Heterodimerization of EGFR with IGF-1R was increased in cetuximab resistant HNSCC cell line UMSCC6. Basal levels of phosphorylated EGFR Y845 showed significant increase in the presence of cetuximab. Surprisingly, this activated Y845 level was not inhibited in the presence of Src inhibitor PP1. Instead, inhibition of IGF-1R by picropodophyllin (PPP) reduced the EGFR Y845 levels. Taken together, these results suggest that heterodimerization of EGFR with IGF-1R can lead to increased activity of EGFR and may be an important platform for cetuximab mediated signaling in head and neck tumors that have become resistant to anti-EGFR therapy.
  
  
  
  EGFR-IGF-1R interaction has a functional consequence of phosphorylation of EGFR Y845 in cetuximab resistant HNSCC cells and dual targeting of EGFR and IGF-1R is a promising therapeutic strategy.
authors.affiliation: Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53792, USA. Giyer@humonc.wisc.edu.
authors.forename: Gopal
authors.identifier: 0000-0002-3138-4882
authors.initials: G
authors.lastname: Iyer
authors.affiliation: Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53792, USA.
authors.forename: James
authors.initials: J
authors.lastname: Price
authors.affiliation: Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53792, USA.
authors.forename: Shay
authors.initials: S
authors.lastname: Bourgeois
authors.affiliation: Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53792, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Armstrong
authors.affiliation: Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53792, USA.
authors.forename: Shyhmin
authors.initials: S
authors.lastname: Huang
authors.affiliation: Department of Human Oncology and the University of Wisconsin School of Medicine and Public Health, University of Wisconsin-Madison, Madison, 53792, USA.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Harari
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D010766:Phosphorylation; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C000597236:IGF1R protein, human; D017451:Receptors, Somatomedin; C512478:EGFR protein, human; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1; D000068818:Cetuximab
keywords: Clinical antibody cetuximab; Head and neck cancer; Heterodimerization; Phosphorylation; Picropodophyllin