The mechanism of action and resistance of sunitinib in RCC.

Abstract

e13606 Background: Sunitinib is considered the first-line therapy for advanced clear cell renal cell carcinoma (ccRCC). However, a complete understanding of its targets and mechanism of action and resistance in ccRCC remains incomplete. The aim of this study was to evaluate the mechanism action of sunitinib and its resistance in RCC and to identify potential targets to overcome sunitinib resistance. Methods: 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. Results: Our studies indicate that sunitinib inhibits ccRCC growth primarily through an anti-angiogenic mechanism and not through direct targeting of ccRCC tumor cells. Higher microvessel density was found in sunitinib-resistant tumors, which indicated that an escape from anti-angiogenesis occurred in these tumors. This escape coincided with increased tumor secretion of interleukin-8 (IL-8) into the plasma. Co-administration of an IL-8 neutralizing antibody resensitized these tumors to sunitinib treatment, demonstrating the functional contribution of IL-8 to sunitinib resistance. Immunohistochemical staining showed that IL-8 expression was elevated in ccRCC tumors from patients who were refractory to sunitinib treatment, indicating IL-8 levels may predict clinical response to sunitinib. Conclusions: In conclusion, our results demonstrate that IL-8 is an important contributor, among others, to sunitinib resistance in ccRCC. IL-8 may serve as a therapeutic target for treatment of sunitinib resistant ccRCC, as well as a biomarker for both acquired and intrinsic sunitinib resistance. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Global Pharmaceuticals