title: Antitumor efficacy of cytotoxic drugs and the monoclonal antibody 806 is enhanced by the EGF receptor inhibitor AG1478.
abstract: Blockade of epidermal growth factor receptor (EGFR) signaling with specific inhibitors of the EGFR tyrosine kinase retards cellular proliferation and arrests the growth of tumor xenografts. AG1478, an inhibitor of the EGFR tyrosine kinase, is used in laboratory studies; however, its therapeutic potential has not been elucidated. Therefore, we evaluated an aqueous form of AG1478 for its antitumor activity in mice bearing human xenografts expressing the WT EGFR or a naturally occurring ligand-independent truncation of the EGFR [delta2-7 (de2-7) EGFR or EGFRvIII]. Parenteral administration of soluble AG1478 blocked phosphorylation of the EGFR at the tumor site and inhibited the growth of A431 xenografts that overexpress the WT EGFR and glioma xenografts expressing the de2-7 EGFR. Strikingly, even subtherapeutic doses of AG1478 significantly enhanced the efficacy of cytotoxic drugs, with the combination of AG1478 and temozolomide displaying synergistic antitumor activity against human glioma xenografts. AG1478 was also examined in combination with mAb 806, an anti-EGFR antibody that was raised against the de2-7 EGFR but unexpectedly also binds a subset of the EGFR expressed in cells exhibiting amplification of the EGFR gene. The combination of AG1478 and mAb 806 displayed additive, and in some cases synergistic, antitumor activity against tumor xenografts overexpressing the EGFR. Here, we demonstrate that different classes of inhibitors to the EGFR can have synergistic antitumor activity in vivo. These results establish the antitumor efficacy of the EGFR inhibitor AG1478 and provide a rationale for its clinical evaluation in combination with both chemotherapy and other EGFR therapeutics.
authors.affiliation: Ludwig Institute for Cancer Research, Austin Hospital, Studley Road, Heidelberg 3084, Australia. terry.johns@ludwig.edu.au
authors.forename: Terrance G
authors.initials: TG
authors.lastname: Johns
authors.forename: Rodney B
authors.initials: RB
authors.lastname: Luwor
authors.forename: Carmel
authors.initials: C
authors.lastname: Murone
authors.forename: Francesca
authors.initials: F
authors.lastname: Walker
authors.forename: Janet
authors.initials: J
authors.lastname: Weinstock
authors.forename: Angela A
authors.initials: AA
authors.lastname: Vitali
authors.forename: Rushika M
authors.initials: RM
authors.lastname: Perera
authors.forename: Achim A
authors.initials: AA
authors.lastname: Jungbluth
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Stockert
authors.forename: Lloyd J
authors.initials: LJ
authors.lastname: Old
authors.forename: Edouard C
authors.initials: EC
authors.lastname: Nice
authors.forename: Antony W
authors.initials: AW
authors.lastname: Burgess
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Scott
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000633:toxicity*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005910:Glioma / Q000188:drug therapy / Q000473:pathology*; D006258:Head and Neck Neoplasms; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D011799:Quinazolines; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D020032:Tyrphostins / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; D020032:Tyrphostins; C101044:RTKI cpd; D066246:ErbB Receptors