Intragenic EGFR and EGFR2 mutations in hepatobiliary tumors and potential role in predicting response to agents that target EGFR

Bekaii‐Saab, Tanios; Sawada, Tetsuji; Williams, Nicole; Frankel, Wendy L.; Plass, Christoph; Villalona‐Calero, Miguel A.; Eng, C. P.

doi:10.1200/jco.2005.23.16_suppl.4037

Cited by 2 publications

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“…Mutational analysis by direct sequencing of PCR products did not reveal any mutations. This is consistent with the results of a study that examined exons 18-21 only in 40 hepatomas and biliary tract cancers [52]. Another alteration is amplification of the EGFR gene, a phenomenon that has been found in 40-50% of glioblastomas, and also in other tumors such as NSCLC and colorectal cancer [53,54].…”

Section: Discussionsupporting

confidence: 86%

Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib

Wiedmann¹,

Feisthammel²,

Blüthner³

et al. 2006

Anti-Cancer Drugs

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Aberrant activation of the epidermal growth factor receptor is frequently observed in neoplasia, notably in tumors of epithelial origin. Attempts to treat such tumors with epidermal growth factor receptor antagonists resulted in remarkable success in recent studies. Little is known, however, about the efficacy of this therapy in biliary tract cancer. Protein expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 was assessed in seven human biliary tract cancer cell lines by immunoblotting. In addition, histological sections from 19 patients with extrahepatic cholangiocarcinoma were analyzed for epidermal growth factor receptor, ErbB-2 and vascular endothelial growth factor receptor-2 expression by immunohistochemistry. Moreover, we sequenced the cDNA products representing the entire epidermal growth factor receptor coding region of the seven cell lines, and searched for genomic epidermal growth factor receptor amplifications and polysomy by fluorescence in-situ hybridization. Cell growth inhibition by gefitinib erlotinib and NVP-AEE788 was studied in vitro by automated cell counting. In addition, the anti-tumoral effect of erlotinib and NVP-AEE788 was studied in a chimeric mouse model. The anti-tumoral drug mechanism in this model was assessed by MIB-1 antibody staining, terminal deoxynucleotidyl transfer-mediated dUTP nick end-labelling assay, von Willebrand factor staining, and immunoblotting for p-p42/44 (p-Erk1/2, p-MAPK) and p-AKT. Immunoblotting revealed expression of epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 in all biliary tract cancer cell lines. EGFR was detectable in six of 19 (32%) extrahepatic human cholangiocarcinoma tissue samples, ErbB-2 in 16 of 19 (84%), and vascular endothelial growth factor receptor-2 in nine of 19 (47%). Neither epidermal growth factor receptor mutations nor amplifications or polysomy were found in the seven biliary tract cancer cell lines. Gefitinib, erlotinib and NVP-AEE788 caused a significant growth inhibition in vitro; however, there was a significant difference in efficacy (NVP-AEE788>erlotinib>gefitinib). After 14 days of in-vivo treatment, using the chimeric mouse model, tumors had a significantly reduced volume and mass after NVP-AEE788, but not after erlotinib treatment, as compared with placebo. Reduction of proliferation (signalling via the mitogen-activated protein kinase pathway), induction of apoptosis and inhibition of angiogenesis were the main mechanisms of drug action. No significant reduction of anti-apoptotic AKT phosphorylation, however, occurred, which may be a possible counter mechanism of the tumor. Epidermal growth factor receptor, ErbB-2, and vascular endothelial growth factor receptor-2 expression was detectable in biliary tract cancer, and receptor inhibition exerts marked effects on tumor growth in vitro and in vivo, which was strongest for the dual EGFR/ErbB-2 inhibitor NVP-AEE788. Therefore, further clinical evaluation of this new drug for the tr...

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Section: Discussionsupporting

confidence: 86%

Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib

Wiedmann¹,

Feisthammel²,

Blüthner³

et al. 2006

Anti-Cancer Drugs

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“…However, Bekaii‐Sabb et al. 12 recently reported a somatic missense mutation in exon 21 of ErbB2 in 11% of HCC specimens. These intriguing findings prompted us to analyze a larger sample size of HCC for ErbB2 mutations in an attempt to identify tumors that may be more responsive to ErbB inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…5 Phase II studies have reported promising activity of ErbB1 and ErbB2 inhibitors in HCC, although we and others have reported low or absent ErbB1 tyrosine kinase domain mutations in HCC. However, Bekaii-Sabb et al 12 recently reported a somatic missense mutation in exon 21 of ErbB2 in 11% of HCC specimens. These intriguing findings prompted us to analyze a larger sample size of HCC for ErbB2 mutations in an attempt to identify tumors that may be more responsive to ErbB inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, Bekaii‐Sabb et al. 12 reported two out of 18 (11%) hepatocellular carcinoma specimens to harbor a somatic missense mutation, H878Y, in exon 21 of ErbB2, although the correlation of this mutation with clinical response to tyrosine kinase inhibitors is as yet unclear. Our work 13 and the work of others has shown activating ErbB1 mutations to be rare or absent in HCC.…”

Section: Introductionmentioning

confidence: 99%

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Lack of somatic ErbB2 tyrosine kinase domain mutations in hepatocellular carcinoma

Wong¹,

Yap²,

Lim³

et al. 2008

Hepatology Research

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Intragenic EGFR and EGFR2 mutations in hepatobiliary tumors and potential role in predicting response to agents that target EGFR

Cited by 2 publications

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Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib

Novel targeted approaches to treating biliary tract cancer: the dual epidermal growth factor receptor and ErbB-2 tyrosine kinase inhibitor NVP-AEE788 is more efficient than the epidermal growth factor receptor inhibitors gefitinib and erlotinib

Lack of somatic ErbB2 tyrosine kinase domain mutations in hepatocellular carcinoma

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