title: Sensitivity and kinase activity of epidermal growth factor receptor (EGFR) exon 19 and others to EGFR-tyrosine kinase inhibitors.
abstract: The presence of epidermal growth factor receptor (EGFR) somatic mutations in non-small-cell lung cancer patients is associated with response to treatment with EGFR-tyrosine kinase inhibitors, such as gefitinib and erlotinib. More than 100 mutations in the kinase domain of EGFR have been identified. In particular there are many variations of deletion mutations in exon 19. In this study, using yellow fluorescent protein-tagged fragments of the EGFR intracellular domain, we examined the differences in sensitivity to gefitinib, erlotinib and afatinib between several exon 19 mutants and other common EGFR mutations. We also used serum of patients undergoing treatment with EGFR-tyrosine kinase inhibitors in this system. In addition, we examined the relative kinase activity of these mutants by measuring relative fluorescent intensity after immunofluorescence staining. We found that both sensitivity to EGFR-tyrosine kinase inhibitors and relative kinase activity differed among several EGFR mutations found in the same region of the kinase domain. This study underscores the importance of reporting the clinical outcome of treatment in relation to different EGFR mutations.
authors: Research Institute for Diseases of the Chest, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors: Kazuto
authors: K
authors: Furuyama
authors: Taishi
authors: T
authors: Harada
authors: Eiji
authors: E
authors: Iwama
authors: Yoshimasa
authors: Y
authors: Shiraishi
authors: Kyoko
authors: K
authors: Okamura
authors: Kayo
authors: K
authors: Ijichi
authors: Akiko
authors: A
authors: Fujii
authors: Keiichi
authors: K
authors: Ota
authors: Shuo
authors: S
authors: Wang
authors: Heyan
authors: H
authors: Li
authors: Koichi
authors: K
authors: Takayama
authors: Giuseppe
authors: G
authors: Giaccone
authors: Yoichi
authors: Y
authors: Nakanishi
mesh_terms: D000077716:Afatinib; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D005091:Exons; D000077156:Gefitinib; D006801:Humans; D061986:MCF-7 Cells; D009154:Mutation; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000077716:Afatinib; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib
references: J Thorac Oncol. 2008 Aug;3(8):832-9
references: 18670300
references: J Clin Oncol. 2002 Nov 1;20(21):4292-302
references: 12409327
references: Clin Cancer Res. 2009 Jan 15;15(2):460-7
references: 19147750
references: N Engl J Med. 2009 Sep 3;361(10):958-67
references: 19692684
references: J Biol Chem. 2000 Dec 8;275(49):38589-96
references: 10991937
references: Cancer Res. 2007 Dec 15;67(24):11924-32
references: 18089823
references: Int J Cancer. 2006 Jan 15;118(2):257-62
references: 16231326
references: Clin Cancer Res. 2011 Jun 1;17(11):3812-21
references: 21531810
references: Cancer Biol Ther. 2007 May;6(5):661-7
references: 17495523
references: N Engl J Med. 2009 Sep 3;361(10):947-57
references: 19692680
references: Cancer Sci. 2007 Dec;98(12):1817-24
references: 17888036
references: Oncogene. 2011 Apr 14;30(15):1744-52
references: 21132006
references: Clin Cancer Res. 2006 Feb 1;12(3 Pt 1):839-44
references: 16467097
references: Clin Cancer Res. 2006 Jul 1;12(13):3908-14
references: 16818686
references: J Clin Oncol. 2010 Sep 1;28(25):3965-72
references: 20679611
references: Clin Cancer Res. 2012 Mar 15;18(6):1790-7
references: 22190593
references: Mol Cancer. 2007 Sep 18;6:56
references: 17877814
references: Clin Cancer Res. 2006 Oct 1;12(19):5764-9
references: 17020982
references: Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11
references: 15329413
references: Mol Cancer Ther. 2012 Mar;11(3):784-91
references: 22228822
references: Lancet Oncol. 2010 Feb;11(2):121-8
references: 20022809
references: Lancet Oncol. 2012 Jan;13(1):e23-31
references: 21764376
references: J Clin Oncol. 2001 Jul 1;19(13):3267-79
references: 11432895
references: J Thorac Oncol. 2011 Feb;6(2):387-92
references: 21252719
references: N Engl J Med. 2005 Feb 24;352(8):786-92
references: 15728811
references: Clin Cancer Res. 2006 Nov 1;12(21):6494-501
references: 17085664
references: Oncogene. 2008 Aug 7;27(34):4702-11
references: 18408761
references: PLoS Med. 2005 Mar;2(3):e73
references: 15737014
references: J Natl Cancer Inst. 2005 Mar 2;97(5):339-46
references: 15741570
references: Clin Cancer Res. 2012 Jun 15;18(12):3470-7
references: 22510346
references: Cancer Sci. 2013 May;104(5):584-9
references: 23387505