title: Amplification of EGFR Wild-Type Alleles in Non-Small Cell Lung Cancer Cells Confers Acquired Resistance to Mutation-Selective EGFR Tyrosine Kinase Inhibitors.
abstract: EGFR-mutated lung cancers account for a significant subgroup of non-small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with minimal effects on wild-type EGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src-AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment.Cancer Res; 77(8); 2078-89. ©2017 AACR.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Shigenari
authors.initials: S
authors.lastname: Nukaga
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan. hiroyukiyasuda@a8.keio.jp ksoejima@cpnet.med.keio.ac.jp ktsuchih@east.ncc.go.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan. hiroyukiyasuda@a8.keio.jp ksoejima@cpnet.med.keio.ac.jp ktsuchih@east.ncc.go.jp.
authors.forename: Katsuya
authors.initials: K
authors.lastname: Tsuchihara
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Hamamoto
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Masuzawa
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kawada
authors.affiliation: Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Naoki
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Mimaki
authors.affiliation: Division of Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, Japan.
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Ikemura
authors.affiliation: Division of Thoracic Oncology, National Cancer Center Hospital East, Chiba, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Goto
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Betsuyaku
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan. hiroyukiyasuda@a8.keio.jp ksoejima@cpnet.med.keio.ac.jp ktsuchih@east.ncc.go.jp.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Soejima
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage / Q000494:pharmacology; D000483:Alleles; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000008:administration & dosage / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D059472:Exome; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology; D011897:Random Allocation; D023041:Xenograft Model Antitumor Assays
chemical_list: D000178:Acrylamides; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C000589977:rociletinib; C512478:EGFR protein, human; D066246:ErbB Receptors; D000068818:Cetuximab