Combined MEK and VEGFR Inhibition in Orthotopic Human Lung Cancer Models Results in Enhanced Inhibition of Tumor Angiogenesis, Growth, and Metastasis

Abstract

Purpose Ras/Raf/MEK/ERK signaling is critical for tumor cell proliferation and survival. Selumetinib is a potent, selective, and orally available MEK1/2 inhibitor. In the current study, we evaluated the therapeutic efficacy of selumetinib alone or with cediranib, an orally available potent inhibitor of all three VEGFR tyrosine kinases, in murine orthotopic NSCLC models. Experimental Design NCI-H441 or NCI-H460 KRAS-mutant human NSCLC cells were injected into the lungs of mice. Mice were randomly assigned to treatment with selumetinib, cediranib, paclitaxel, selumetinib plus cediranib, or control. When controls became moribund, all animals were sacrificed and assessed for lung tumor burden and locoregional metastasis. Lung tumors and adjacent normal tissues were subjected to immunohistochemical analyses. Results Selumetinib inhibited lung tumor growth and, particularly at higher dose, reduced locoregional metastasis, as did cediranib. Combining selumetinib and cediranib markedly enhanced their antitumor effects, with near complete suppression of metastasis. Immunohistochemistry of tumor tissues revealed that selumetinib alone or with cediranib reduced ERK phosphorylation, angiogenesis, and tumor cell proliferation and increased apoptosis. The antiangiogenic and apoptotic effects were substantially enhanced when the agents were combined. Selumetinib also inhibited lung tumor VEGF production and VEGFR signaling. Conclusions In the current study, we evaluated therapy directed against MEK combined with antiangiogenic therapy in distinct orthotopic NSCLC models. MEK inhibition resulted in potent antiangiogenic effects with decreased VEGF expression and signaling. Combining selumetinib with cediranib enhanced their anti-tumor and antiangiogenic effects. We conclude that combining selumetinib and cediranib represents a promising strategy for the treatment of NSCLC.

Tumor VEGF:VEGFR2 autocrine feed-forward loop triggers angiogenesis in lung cancer

“…In accordance with our xenograft data, combined PD0325901 and ZD6474 treatment resulted in substantial tumor regression, as detected by bioluminescence imaging (BLI) ( Figure 5). These findings support the hypothesis of a recent study that combined MEK and VEGFR inhibition enhances inhibition of tumor growth (19). Of note, complete tumor shrinkage was associated with the expression levels of VEGFR2 on tumor cells.…”

Rational combination therapy with PARP and MEK inhibitors capitalizes on therapeutic liabilities in RAS mutant cancers

“…S8B). The observations that mutant RAS induces VEGF production and that VEGFR signals through the RAS/MAPK pathway (40, 41) could contribute to decreases in vascularity observed with PARPi and MEKi combinations. Indeed, VEGF expression is dependent on RAS pathway activity in multiple RAS -mutant cell line models (fig.…”

In vivo antitumor effect of endostatin-loaded chitosan nanoparticles combined with paclitaxel on Lewis lung carcinoma

“…However, inadequate tumor vascularization leads to the inefficient distribution of drugs in tumor cells, which is an important obstacle to anticancer therapies (Shi et al, 2013). The vascular normalization theory posits that using inhibitors of vascular endothelial growth factor (VEGF) signaling in combination with chemotherapeutics can increase antitumor efficacy (Ferrara & Kerbel, 2005;Takahashi et al, 2012;Klose et al, 2016). Clinical trials have shown that the chemotherapeutic agent PTX combined with the antiangiogenic peptide endostatin (ES) improves clinical therapeutic efficacy in advanced NSCLC patients without unacceptable toxicity (Han et al, 2011;Sun et al, 2016).…”