title: Targeting EGFR in bladder cancer.
abstract: Expression and overexpression of the epidermal growth factor receptor (EGFR) have been described in several solid tumors including bladder, breast, colorectal, NSCLC, prostate, and ovarian cancers. In addition to gene amplification, point mutations within the kinase domain also occur. Previous reports indicate that the patient's response to gefitinib depends on either the presence of mutations within the kinase domain of EGFR or the expression of the most frequent alteration, the truncated EGFR variant III (EGFRvIII). Therefore, it is important to determine if these EGFR alterations are present in urothelial carcinoma. The kinase domain of EGFR (exons 18-21) from 11 bladder cancer cell lines as well as from 75 patient tumors was analyzed by automated sequencing. No mutations were detected in all samples tested. Furthermore, analysis of EGFRvIII by immunohistochemistry revealed that almost half of all the patient samples expressed this truncation in a urothelial carcinoma tissue microarray. However, there have been previous reports of inconsistencies in detecting EGFRvIII by immunohistochemistry owing to the specificity of the antibodies and the methodologies utilized. Therefore, these results were validated by reverse transcription PCR, real-time PCR and western blot analysis. In these assays, none of the samples tested positive for EGFRvIII. Taken together, these results indicate that mutations within the tyrosine kinase domain of EGFR and expression of EGFRvIII are rare events in bladder cancer and therefore do not contribute to the malignant phenotype of this tumor. These results have clinical implications in selecting tyrosine kinase inhibitors for the therapy of urothelial carcinoma.
authors: Department of Cancer Biology, U.T. MD Anderson Cancer Center, Houston, TX, USA.
authors: G J
authors: GJ
authors: Villares
authors: M
authors: M
authors: Zigler
authors: K
authors: K
authors: Blehm
authors: C
authors: C
authors: Bogdan
authors: D
authors: D
authors: McConkey
authors: D
authors: D
authors: Colin
authors: Menashe
authors: M
authors: Bar-Eli
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000032:analysis*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation; D016133:Polymerase Chain Reaction; D012334:RNA, Neoplasm / Q000032:analysis*; D046888:Tissue Array Analysis; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D012334:RNA, Neoplasm; C410723:epidermal growth factor receptor VIII; D066246:ErbB Receptors
references: J Natl Cancer Inst. 2005 May 4;97(9):643-55
references: 15870435
references: J Urol. 1995 Mar;153(3 Pt 2):919-25
references: 7853575
references: J Biol Chem. 1990 May 15;265(14):7709-12
references: 2186024
references: Oncologist. 2007 Feb;12(2):201-10
references: 17296816
references: J Urol. 1995 Oct;154(4):1532-8
references: 7658585
references: Int J Cancer. 2002 Sep 10;101(2):111-7
references: 12209987
references: Breast Cancer Res Treat. 2004 Sep;87(1):87-95
references: 15377854
references: Cancer Res. 1990 Dec 15;50(24):8017-22
references: 2253244
references: Clin Cancer Res. 1999 Feb;5(2):257-65
references: 10037173
references: Cancer Res. 1995 Jul 15;55(14):3140-8
references: 7606735
references: Proc Natl Acad Sci U S A. 1994 Aug 2;91(16):7727-31
references: 8052651
references: Clin Cancer Res. 2004 May 1;10(9):3216-24
references: 15131063
references: Oncogene. 1996 Jul 4;13(1):85-96
references: 8700557
references: Biochem J. 1997 Jun 15;324 ( Pt 3):855-61
references: 9210410
references: Crit Rev Oncol Hematol. 2003 Jun 27;46 Suppl:S85-104
references: 12850530
references: J Biol Chem. 1997 Jan 31;272(5):2927-35
references: 9006938
references: Cancer Res. 1995 Dec 1;55(23):5536-9
references: 7585629
references: Cell Growth Differ. 1995 Oct;6(10):1251-9
references: 8845302
references: J Biol Chem. 1998 Jan 2;273(1):200-6
references: 9417065
references: Lab Invest. 2005 Apr;85(4):532-49
references: 15778693
references: Eur Urol. 1999 Nov;36(5):393-400
references: 10516448
references: J Biol Chem. 1996 Oct 11;271(41):25639-45
references: 8810340
references: N Engl J Med. 2004 May 20;350(21):2129-39
references: 15118073
references: J Biol Chem. 2005 Feb 4;280(5):3414-25
references: 15557335
references: Nat Rev Mol Cell Biol. 2001 Feb;2(2):127-37
references: 11252954
references: Curr Opin Urol. 2004 Sep;14(5):295-300
references: 15300150
references: BJU Int. 1999 Mar;83(4):498-503
references: 10210578
references: Ann Oncol. 1997 Dec;8(12):1197-206
references: 9496384
references: Cancer Res. 1993 Jul 15;53(14):3217-20
references: 8391918
references: Cancer Res. 2007 Feb 15;67(4):1430-5
references: 17308080
references: Proc Natl Acad Sci U S A. 1990 Nov;87(21):8602-6
references: 2236070
references: Cancer Res. 2005 Nov 15;65(22):10524-35
references: 16288045
references: Br J Cancer. 2005 Oct 17;93(8):915-23
references: 16189524
references: Cancer Res. 1995 Oct 1;55(19):4375-82
references: 7671250
references: Clin Cancer Res. 2006 Aug 1;12(15):4671-7
references: 16899617