title: In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer.
abstract: EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the "therapeutic window" of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1st (erlotinib), 2nd (afatinib) and 3rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR. An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1st and 2nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yasuda
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Tani
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: Ayano
authors.initials: A
authors.lastname: Oashi
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Kota
authors.initials: K
authors.lastname: Ishioka
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Arai
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.
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Miyawaki
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 Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Costa
authors.affiliation: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Susumu S
authors.initials: SS
authors.lastname: Kobayashi
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.
authors.forename: Kenzo
authors.initials: K
authors.lastname: Soejima
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics*; D005091:Exons; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR exon 20 insertion mutations; EGFR mutation; EGFR tyrosine kinase inhibitors; in vitro modeling; lung cancer