Conclusions
Fulvestrant may enhance effects of vandetanib in NSCLC by blocking estrogen-driven activation of the EGFR pathway.
Methods
We examined activation of EGFR and expression of VEGF in response to β-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 β-estradiol-induced P-MAPK activation, demonstrating that vandetanib blocks β-estradiol-induced EGFR signaling. Treatment with β-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 ERβ 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.