Abstract
Abstract Treatment with inhibitors that block vascular endothelial growth factor (VEGF) signaling can make tumors more aggressive in preclinical models. The mechanism underlying this form of resistance is not fully understood, but vascular pruning, intratumoral hypoxia, and increased expression of c-MET, the tyrosine kinase receptor for hepatocyte growth factor (HGF), could be contributing factors. We found that treatment of pancreatic neuroendocrine tumors in RIP-Tag2 mice with a neutralizing anti-VEGF antibody or with sunitinib, a receptor tyrosine kinase inhibitor that blocks VEGFR and related receptors, reduced tumor burden and vascularity but increased intratumoral hypoxia, HIF-1alpha, and expression and activation of c-MET. Invasion into the exocrine pancreas and metastasis to the liver also increased. Importantly, administration of either of two c-MET inhibitors, PF-04217903 or crizotinib (PF-02341066), together with anti-VEGF therapy reduced tumor growth and vascularity and also significantly decreased local invasion and liver metastasis. Similar benefits were found after treatment with cabozantinib (XL184), a multitargeted tyrosine kinase inhibitor that simultaneously blocks c-MET and VEGF receptors. Together, these results indicate that inhibition of VEGF signaling can promote vascular pruning, intratumoral hypoxia, HIF-1alpha accumulation, and activation of c-MET. Concurrent inhibition of c-MET and VEGF signaling not only can slow tumor growth but also can reduce invasion and metastasis. Inhibition of c-MET and VEGF signaling pathways together combines the favorable tumor growth-slowing effects of inhibiting angiogenesis with suppression of invasion and metastasis, despite the intratumoral hypoxia due to vascular pruning. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-315. doi:1538-7445.AM2012-LB-315
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