title: EGFR Exon 18 Mutations in Lung Cancer: Molecular Predictors of Augmented Sensitivity to Afatinib or Neratinib as Compared with First- or Third-Generation TKIs.
abstract: OBJECTIVE
  Lung cancers harboring common EGFR mutations respond to EGFR tyrosine kinase inhibitors (TKI), whereas exon 20 insertions (Ins20) are resistant to them. However, little is known about mutations in exon 18.
  
  
  METHODS
  Mutational status of lung cancers between 2001 and 2015 was reviewed. Three representative mutations in exon 18, G719A, E709K, and exon 18 deletion (Del18: delE709_T710insD) were retrovirally introduced into Ba/F3 and NIH/3T3 cells. The 90% inhibitory concentrations (IC90s) of first-generation (1G; gefitinib and erlotinib), second-generation (2G; afatinib, dacomitinib, and neratinib), and third-generation TKIs (3G; AZD9291 and CO1686) were determined.
  
  
  RESULTS
  Among 1,402 EGFR mutations, Del19, L858R, and Ins20 were detected in 40%, 47%, and 4%, respectively. Exon 18 mutations, including G719X, E709X, and Del18, were present in 3.2%. Transfected Ba/F3 cells grew in the absence of IL3, and NIH/3T3 cells formed foci with marked pile-up, indicating their oncogenic abilities. IC90s of 1G and 3G TKIs in G719A, E709K, and Del18 were much higher than those in Del19 (by >11-50-fold), whereas IC90s of afatinib were only 3- to 7-fold greater than those for Del19. Notably, cells transfected with G719A and E709K exhibited higher sensitivity to neratinib (by 5-25-fold) than those expressing Del19. Patients with lung cancers harboring G719X exhibited higher response rate to afatinib or neratinib (∼ 80%) than to 1G TKIs (35%-56%) by compilation of data in the literature.
  
  
  CONCLUSIONS
  Lung cancers harboring exon 18 mutations should not be overlooked in clinical practice. These cases can be best treated with afatinib or neratinib, although the currently available in vitro diagnostic kits cannot detect all exon 18 mutations.
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Togashi
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yatabe
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. Department of Thoracic Surgery, Kitakyushu Municipal Medical Center, Kitakyushu, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuuchi
authors.affiliation: Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan. Department of Respiratory Medicine, Nagoya City East Medical Center, Nagoya, Japan.
authors.forename: Park
authors.initials: P
authors.lastname: Jangchul
authors.affiliation: Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Chiaki
authors.initials: C
authors.lastname: Kondo
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimoji
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Sato
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suda
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomizawa
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Hida
authors.affiliation: Department of Genome Biology, Kinki University Faculty of Medicine, Osaka-Sayama, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Nishio
authors.affiliation: Department of Thoracic Surgery, Kinki University Faculty of Medicine, Osaka-Sayama, Japan. mitsudom@surg.med.kindai.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
mesh_terms: D000077716:Afatinib; D000818:Animals; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D030541:Databases, Genetic; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics*; D005091:Exons; D015870:Gene Expression; D005787:Gene Frequency; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D008958:Models, Molecular; D008968:Molecular Conformation; D009154:Mutation; D059645:Mutation Rate; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D014162:Transfection; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D011804:Quinolines; D000077716:Afatinib; D066246:ErbB Receptors; C487932:neratinib