Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma

D. Yoshikawa, Hidenori Ojima, A. Kokubu, T. Ochiya, S. Kasai, S. Hirohashi, T. Shibata

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

Cholangiocarcinoma is an intractable cancer, with no effective therapy other than surgical resection. Elevated vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expressions are associated with the progression of cholangiocarcinoma. We therefore examined whether inhibition of VEGFR and EGFR could be a potential therapeutic target for cholangiocarcinoma. Vandetanib (ZD6474, ZACTIMA), a VEGFR-2/EGFR inhibitor, was evaluated. Four human cholangiocarcinoma cell lines were molecularly characterised and investigated for their response to vandetanib. In vitro, two cell lines (OZ and HuCCT1), both of which harboured KRAS mutation, were refractory to vandetanib, one cell line (TGBC24TKB) was somewhat resistant, and another cell line (TKKK) was sensitive. The most sensitive cell line (TKKK) had EGFR amplification. Vandetanib significantly inhibited the growth of TKKK xenografts at doses 12.5 mg kg 1 day 1 (P0.05), but higher doses (50 mg kg 1 day 1, P0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg 1 day 1) also significantly (P0.006) prolonged the time to metastasis in an intravenous model of TKKK metastasis. Inhibiting both VEGFR and EGFR signalling appears a promising therapeutic approach for cholangiocarcinoma. The absence of KRAS mutation and the presence of EGFR amplification may be potential predictive molecular marker of sensitivity to EGFR-targeted therapy in cholangiocarcinoma.

Original languageEnglish
Pages (from-to)1257-1266
Number of pages10
JournalBritish Journal of Cancer
Volume100
Issue number8
DOIs
Publication statusPublished - 2009 Apr 21
Externally publishedYes

Fingerprint

Molecular Targeted Therapy
Cholangiocarcinoma
Epidermal Growth Factor Receptor
Cell Line
Heterografts
Neoplasm Metastasis
Vascular Endothelial Growth Factor Receptor-2
Mutation
Therapeutics
Growth
N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methylpiperidin-4-yl)methoxy)quinazolin-4-amine
Vascular Endothelial Growth Factor A

Keywords

  • Cholangiocarcinoma
  • EGFR
  • In vivo imaging
  • Molecular-targeted therapy
  • VEGFR

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. / Yoshikawa, D.; Ojima, Hidenori; Kokubu, A.; Ochiya, T.; Kasai, S.; Hirohashi, S.; Shibata, T.

In: British Journal of Cancer, Vol. 100, No. 8, 21.04.2009, p. 1257-1266.

Research output: Contribution to journalArticle

Yoshikawa, D. ; Ojima, Hidenori ; Kokubu, A. ; Ochiya, T. ; Kasai, S. ; Hirohashi, S. ; Shibata, T. / Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma. In: British Journal of Cancer. 2009 ; Vol. 100, No. 8. pp. 1257-1266.
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