Vandetanib inhibits both VEGFR-2 and EGFR signalling at clinically relevant drug levels in preclinical models of human cancer

Abstract

Abstract.Vandetanib is a multi-targeted receptor tyrosine kinase inhibitor that is in clinical development for the treatment of solid tumours. This preclinical study examined the inhibition of two key signalling pathways (VEGFR-2, EGFR) at drug concentrations similar to those achieved in the clinic, and their contribution to direct and indirect antitumour effects of vandetanib. For in vitro studies, receptor phosphorylation was assessed by Western blotting and ELISA, cell proliferation was assessed using a cell viability endpoint, and effects on cell cycle determined using flow cytometry. For in vivo studies, Western blotting, ELISA and immunohistochemistry (IHC) were used to assess receptor phosphorylation. Cell culture experiments demonstrated that anti-proliferative effects of vandetanib resulted from inhibition of either EGFR or VEGFR-2 signalling in endothelial cells, but were associated with inhibition of EGFR signalling in tumour cells. Vandetanib inhibited both EGFR and VEGFR-2 signalling in normal lung tissue and in tumour xenografts. In a lung cancer model expressing an activating EGFR mutation, the activity of vandetanib was similar to that of a highly selective EGFR inhibitor (gefitinib), and markedly greater than that of a highly selective VEGFR inhibitor (vatalanib). These data suggest that at the plasma exposures achieved in the clinic, vandetanib will significantly inhibit both VEGFR-2 and EGFR signalling, and that both inhibition of angiogenesis and direct inhibition of tumour cell growth can contribute to treatment response. IntroductionVandetanib (ZD6474) was identified as a potent nanomolar inhibitor of vascular endothelial growth factor (VEGF) signalling with pharmacokinetic properties compatible with chronic, once daily, oral dosing (1,2). Although the compound was also known to be a sub-micromolar inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, the early preclinical evidence suggested that this activity is not essential for antitumour effects in vivo since vandetanib demonstrated significant inhibitory activity against a histologically diverse panel of human tumour xenografts, including models insensitive to gefitinib, a highly selective EGFR tyrosine kinase inhibitor (TKI) (1,3). In the clinic, vandetanib has shown activity in non-small cell lung cancer (NSCLC) both as monotherapy and in combination with chemotherapy (4-6). Vandetanib monotherapy has an acceptable safety and tolerability profile at doses of up to 300 mg/day, where the steady-state mean plasma drug concentration is approximately 1000 ng/ml (2.2 µM; range 1.6-6.3 µM), and where adverse events included hypertension, rash and diarrhoea (7,8) which is consistent with pharmacological inhibition of both VEGFR receptor-2 (VEGFR-2) and EGFR in normal tissues.Although there has been some success in identifying biomarkers of differential benefit to selective EGFR signalling inhibitors (9), no predictive biomarkers have yet been identified for VEGF-signalling inhibitors (10). Identifying biomarkers of benefit fr...

The anti-neoplastic activity of Vandetanib against high-risk medulloblastoma variants is profoundly enhanced by additional PI3K inhibition

“…The efficacy of Vandetanib has been suggested to rely not solely on inhibition of angiogenesis but also on direct attenuation of tumor growth by blockade of its target receptors namely vascular, endothelial growth factor receptor 2 and 3, epidermal growth factor receptor (EGFR) and c-RET expressed on the cancer cells themselves. [ 9 – 11 ]. VEGFR-2 and EGFR receptors have recently been identified as medulloblastoma oncogenes with EGFR gene amplification and overexpression being a marker of poor prognosis [ 12 – 16 ].…”

EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second-line treatment of patients with advanced non-small cell lung cancer

“…Since vandetanib simultaneously inhibits both EGFR and VEGFR2 signaling [21], it is not possible in the present study to determine whether the biomarkers are of benefit from pharmacological inhibition of one or both of these targets, although the association between benefit from vandetanib and EGFR biomarkers suggests that the activity of the drug is mediated, at least in part, through inhibition of EGFR. However, in the randomized phase III BETA study comparing the combination of erlotinib and bevacizumab with erlotinib alone, the EGFR mutant subgroup appeared to derive greater benefit from the addition of bevacizumab suggesting that dual blockade of the VEGF and EGFR pathways may be particularly active in EGFR MT+ tumors [22].…”

Combining molecular targeted agents with radiation therapy for malignant gliomas

“…Vandetanib is an oral anilinoquinazoline compound with a low molecular weight that acts as a potent multitargeted inhibitor of VEGFR-2,50 EGFR, and the REarranged during Transfection (RET) tyrosine kinases 51,52. Therefore, by simultaneous inhibition of both VEGFR and EGFR pathways, vandetanib may exhibit antitumor activity through blockade of multiple mechanisms that are essentials for tumor angiogenesis and proliferation.…”