Abstract 1644: Sunitinib primarily acts on tumor endothelium but not tumor cells to inhibit renal cell carcinoma tumor growth

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Sunitinib, a small-molecule inhibitor of multiple receptor tyrosine kinases (RTKs), is considered the standard of care for first line therapy of advanced clear cell renal cell carcinoma (ccRCC). However, a complete understanding of its targets and mechanism of action in the treatment of ccRCC remains incomplete. We aimed to evaluate the primary targets of sunitinib in the treatment of ccRCC (i.e. tumor cells versus endothelial cells) and to determine which RTK(s) specifically contribute to the therapeutic effect of sunitinib. Microarray gene expression profiling of human ccRCC samples showed that, of the known RTK targets of sunitinib, only PDGFR-β and VEGFR-2 were overexpressed in ccRCC relative to normal tissues. Western blotting of ccRCC and endothelial cell lines confirmed that PDGFR and VEGFR, but not other sunitinib targets, were expressed in these cells. In vitro studies found that sunitinib was unable to inhibit survival or proliferation of ccRCC cells at pharmacologically relevant concentrations (∼0.1 μM) which inhibit RTK targets. In contrast, sunitinib inhibited endothelial cell proliferation and invasion at these concentrations through suppression of VEGFR-2 signaling. Sunitinib inhibited growth of ccRCC xenografts and decreased tumor microvessel density as soon as 12 hours post-treatment; however, sunitinib showed no significant effects on tumor cell proliferation or apoptosis after up to 72 hours post-treatment. Our studies indicate that sunitinib inhibits ccRCC growth primarily through an anti-angiogenic mechanism and not through direct targeting of ccRCC tumor cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1644.