title: Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.
abstract: EGFR is a major anticancer drug target in human epithelial tumors. One effective class of agents is the tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib. These drugs induce dramatic responses in individuals with lung adenocarcinomas characterized by mutations in exons encoding the EGFR tyrosine kinase domain, but disease progression invariably occurs. A major reason for such acquired resistance is the outgrowth of tumor cells with additional TKI-resistant EGFR mutations. Here we used relevant transgenic mouse lung tumor models to evaluate strategies to overcome the most common EGFR TKI resistance mutation, T790M. We treated mice bearing tumors harboring EGFR mutations with a variety of anticancer agents, including a new irreversible EGFR TKI that is under development (BIBW-2992) and the EGFR-specific antibody cetuximab. Surprisingly, we found that only the combination of both agents together induced dramatic shrinkage of erlotinib-resistant tumors harboring the T790M mutation, because together they efficiently depleted both phosphorylated and total EGFR. We suggest that these studies have immediate therapeutic implications for lung cancer patients, as dual targeting with cetuximab and a second-generation EGFR TKI may be an effective strategy to overcome T790M-mediated drug resistance. Moreover, this approach could serve as an important model for targeting other receptor tyrosine kinases activated in human cancers.
authors.affiliation: Pao Laboratory, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: Lucia
authors.initials: L
authors.lastname: Regales
authors.forename: Yixuan
authors.initials: Y
authors.lastname: Gong
authors.forename: Ronglai
authors.initials: R
authors.lastname: Shen
authors.forename: Elisa
authors.initials: E
authors.lastname: de Stanchina
authors.forename: Igor
authors.initials: I
authors.lastname: Vivanco
authors.forename: Aviva
authors.initials: A
authors.lastname: Goel
authors.forename: Jason A
authors.initials: JA
authors.lastname: Koutcher
authors.forename: Maria
authors.initials: M
authors.lastname: Spassova
authors.forename: Ouathek
authors.initials: O
authors.lastname: Ouerfelli
authors.forename: Ingo K
authors.initials: IK
authors.lastname: Mellinghoff
authors.forename: Maureen F
authors.initials: MF
authors.lastname: Zakowski
authors.forename: Katerina A
authors.initials: KA
authors.lastname: Politi
authors.forename: William
authors.initials: W
authors.lastname: Pao
mesh_terms: D000077716:Afatinib; D066258:Amphiregulin; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066255:EGF Family of Proteins; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism; D066260:Epiregulin; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D009154:Mutation; D009368:Neoplasm Transplantation; D017239:Paclitaxel / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000378:metabolism* / Q000627:therapeutic use; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C587848:AREG protein, human; D066258:Amphiregulin; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; C587849:Areg protein, mouse; D066255:EGF Family of Proteins; C587880:EREG protein, human; D066260:Epiregulin; C587881:Ereg protein, mouse; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017239:Paclitaxel; D000068818:Cetuximab