Multiple factors can contribute to evasive resistance that develops during treatment with angiogenesis inhibitors that target the vascular endothelial growth factor (VEGF) pathway. Evidence from studies of neuroendocrine tumors in RIP-Tag2 transgenic mice indicates that hypoxia-induced activation of pro-invasive pathways involving the receptor for hepatocyte growth factor, c-Met, can participate. The present study sought to determine whether this mechanism also applies to other types of tumors. Our approach was to ask whether growth and invasiveness of Panc-1 pancreatic adenocarcinomas implanted orthotopically in nude mice were reduced by inhibition of c-Met during concurrent treatment with an angiogenesis inhibitor for 3 weeks. Panc-1 tumors in mice treated with the angiogenesis inhibitor sunitinib, a tyrosine kinase inhibitor that blocks VEGFR and related receptors, had a 75% reduction in vascularity and grew more slowly than controls but had twice as much of intratumoral hypoxia, assessed by pimonidazole staining. Unlike the faint c-Met immunoreactivity in most tumor cells of vehicle-treated Panc-1 tumors, c-Met staining was stronger in tumor cells after treatment with sunitinib. Tumors in mice treated with the selective c-Met inhibitor PF-04217903 alone had little change in tumor vascularity or intratumoral hypoxia and grew faster than those treated with sunitinib. However, tumors treated with sunitinib plus PF-04217903 together grew more slowly than after sunitinib alone but had similar amounts of vascular pruning and hypoxia. Tumor invasiveness, reflected by amylase-positive acinar cells of the exocrine pancreas located within tumors, was exaggerated after sunitinib treatment but, importantly, was significantly less in tumors treated with sunitinib plus PF-04217903. These findings indicate that sunitinib used alone reduced the growth of Panc-1 tumors but increased intratumoral hypoxia, c-Met expression, and local invasion into the surrounding normal pancreas. By comparison, sunitinib administered concurrently with the c-Met inhibitor PF-04217903 resulted in further slowing of tumor growth and less tumor invasiveness.

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 1378. doi:1538-7445.AM2012-1378