Dataset Information
Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer.
Ontology highlight
ABSTRACT: Introduction
Estrogen is known to promote proliferation and to activate the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) is a known estrogen responsive gene in breast cancer. We sought to determine whether the VEGF pathway is also regulated by estrogen in lung cancer cells, and whether combining an inhibitor of the ER pathway with a dual vascular endothelial growth factor receptor (VEGFR)/EGFR inhibitor would show enhanced antitumor effects.Methods
We examined activation of EGFR and expression of VEGF in response to ?-estradiol, and the antitumor activity of the multitargeted VEGFR/EGFR/RET inhibitor, vandetanib, when combined with the antiestrogen fulvestrant both in vitro and in vivo.Results
NSCLC cells expressed VEGFR-3 and EGFR. Vandetanib treatment of NSCLC cells resulted in inhibition of EGFR and VEGFR-3 and inhibition of ?-estradiol-induced P-MAPK activation, demonstrating that vandetanib blocks ?-estradiol-induced EGFR signaling. Treatment with ?-estradiol stimulated VEGFA mRNA and protein (p < 0.0001 over baseline), suggesting estrogenic signaling causes heightened VEGFA pathway activation. This estrogenic induction of VEGFA mRNA seems largely dependent on cross-talk with EGFR. Long-term vandetanib treatment also significantly increased ER? protein expression. The combination of vandetanib with fulvestrant maximally inhibited cell growth compared with single agents (p < 0.0001) and decreased tumor xenograft volume by 64%, compared with 51% for vandetanib (p < 0.05) and 23% for fulvestrant (p < 0.005). Antitumor effects of combination therapy were accompanied by a significant increase in apoptotic cells compared with single agents.Conclusions
Fulvestrant may enhance effects of vandetanib in NSCLC by blocking estrogen-driven activation of the EGFR pathway.
SUBMITTER: Siegfried JM
PROVIDER: S-EPMC3288546 | biostudies-literature | 2012 Mar
REPOSITORIES: biostudies-literature
Publications
Combining the multitargeted tyrosine kinase inhibitor vandetanib with the antiestrogen fulvestrant enhances its antitumor effect in non-small cell lung cancer.
Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 20120301 3
<h4>Introduction</h4>Estrogen is known to promote proliferation and to activate the epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Vascular endothelial growth factor (VEGF) is a known estrogen responsive gene in breast cancer. We sought to determine whether the VEGF pathway is also regulated by estrogen in lung cancer cells, and whether combining an inhibitor of the ER pathway with a dual vascular endothelial growth factor receptor (VEGFR)/EGFR inhibitor would sho ...[more]
