RRC ID 67408
Author Kobayashi Y, Togashi Y, Yatabe Y, Mizuuchi H, Jangchul P, Kondo C, Shimoji M, Sato K, Suda K, Tomizawa K, Takemoto T, Hida T, Nishio K, Mitsudomi T.
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.
Journal Clin Cancer Res
Abstract PURPOSE: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.
EXPERIMENTAL DESIGN: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.
Volume 21(23)
Pages 5305-13
Published 2015-12-1
DOI 10.1158/1078-0432.CCR-15-1046
PII 1078-0432.CCR-15-1046
PMID 26206867
MeSH Afatinib Animals Cell Line, Tumor DNA Mutational Analysis Databases, Genetic Drug Resistance, Neoplasm / genetics ErbB Receptors / chemistry ErbB Receptors / genetics* Exons* Gene Expression Gene Frequency Humans Lung Neoplasms / drug therapy Lung Neoplasms / genetics* Lung Neoplasms / pathology Male Mice Middle Aged Models, Molecular Molecular Conformation Mutation* Mutation Rate Protein Kinase Inhibitors / chemistry Protein Kinase Inhibitors / pharmacology Protein Kinase Inhibitors / therapeutic use Quinazolines / chemistry Quinazolines / pharmacology Quinazolines / therapeutic use Quinolines / chemistry Quinolines / pharmacology Quinolines / therapeutic use Structure-Activity Relationship Transfection Treatment Outcome
IF 10.107
Human and Animal Cells Ba/F3(RCB0805) WEHI-3(RCB0035)