Abstract 629: MEK inhibition by selumetinib (AZD6244) inhibits progression with a multicentric antiangiogenic effect and enhances the efficacy of cediranib in orthotopic human lung cancer models

Abstract

Abstract Background: Selumetinib is a potent orally available MEK 1/2 inhibitor now in clinical development. We evaluated the therapeutic efficacy of selumetinib alone or with cediranib (RECENTIN™), an orally available inhibitor of all 3 VEGFR tyrosine kinases, in distinct K-ras mutant orthotopic human non-small cell lung cancer models. Methods: NCI-H441 or NCI-H460 cells were injected into the lungs of mice. Mice were randomized to treatment with selumetinib (12.5 or 25 mg/kg/BID po), cediranib (3 mg/kg/qd po), paclitaxel (200 µg/week ip), selumetinib + cediranib, or vehicle. When controls became moribund, all mice were sacrificed and assessed and lung tumors subjected to immunohistochemical analyses. Results: In both models, selumetinib or cediranib were well tolerated and inhibited tumor growth and metastasis with efficacy superior to paclitaxel. The combined antitumor effects of selumetinib and cediranib were markedly enhanced with near complete metastasis suppression. Immunohistochemistry revealed that cediranib or selumetinib reduced microvessel density and tumor cell proliferation and increased apoptosis, with no effect on VEGFR2 expression. The effects were substantially enhanced when they were combined. Cediranib blocked VEGFR2 activation. Selumetinib's antiangiogenic effect, but not cediranib's, was associated with reduced VEGF expression, particularly in the H441 model. Surprisingly, selumetinib reduced tumor and endothelial VEGFR2 activation, which may in part be due to the offset of VEGF expression. Conclusions: The combination of selumetinib and cediranib enhances their antitumor, antimetastatic, and antiangiogenic effects. Selumetinib decreased VEGF and suppressed VEGFR activation, suggesting that MEK inhibition targets VEGF-driven angiogenesis at multiple levels. These data provide a strong basis for clinical trials of selumetinib and cediranib in lung cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 629. doi:10.1158/1538-7445.AM2011-629