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

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 X12.5 mg kg À1 day À1 (Po0.05), but higher doses (50 mg kg À1 day À1 , Po0.05) of vandetanib were required to inhibit the growth of OZ xenografts. Vandetanib (25 mg kg À1 day À1 ) also significantly (P ¼ 0.006) 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.

Biliary cancer: intrahepatic cholangiocarcinoma vs. extrahepatic cholangiocarcinoma vs. gallbladder cancers: classification and therapeutic implications

“…The EGFR signaling pathway is integral in epithelial cell growth and proliferation, where preclinical studies have shown tumor regression with EGFR inhibition (28,30), forming the rationale for targeting EGFR for treatment. While initial small studies demonstrated promising antitumor activity with anti-EGFR therapy in combination with gemcitabine-based chemotherapy (31,32), these findings were unable to translate into a significant clinical benefit in larger randomized clinical trials (33,34 (35,36).…”

The Role of the Tumor Microenvironment in the Pathogenesis of Cholangiocarcinoma

“…In support of this notion, inhibition of VEGFR and EGFR signaling with vandetanib (ZD6474, a tyrosine kinase inhibitor) can be an important approach for the management of the subset of cholangiocarcinoma that lack KRAS mutations and/or have EGFR amplification (Yoshikawa et al 2009). Furthermore, ZD1839 (IRESSA), an orally active, selective inhibitor of EGFR tyrosine kinase has clinical activity against cholangiocarcinoma by stabilizing the cell cycle inhibitor, p27Kip1 and enhancing radiosensitivity in cholangiocarcinoma cell lines (Yabuuchi et al 2009).…”

“…The factors that drive angiogenesis have also been shown to have distinct effects on cholangiocyte and cholangiocarcinoma growth in an autocrine manner Tang et al 2006;Mobius et al 2007;Yabuuchi et al 2009;Yoshikawa et al 2009;Glaser et al 2010). Indeed, the proliferative effects of estrogen on cholangiocarcinoma cell lines have been attributed to a mechanism involving the upregulation of VEGF expression, as blocking VEGF ameliorates the estrogenic effects on proliferation (Mancino et al 2009).…”

Targeted therapy for biliary-tract cancer

“…In an examination conducted using human cholangiocarcinoma cell lines, ZD6474, an inhibitor of VEGFR and EGFR signaling, showed promising anticancer activity [32]. This study revealed that the absence of KRAS mutation and presence of EGFR amplification may be potentially predictive molecular markers of the sensitivity of cholangiocarcinoma to EGFR-targeted therapy [32].…”