Abstract 1377: Characterisation of mechanisms of resistance to sunitinib in a unique pre-clinical RCC model

Abstract

Abstract Background: Resistance to sunitinib, a broad spectrum tyrosine kinase inhibitor considered as first-line therapy for advanced clear cell renal carcinoma (ccRCC), is almost inevitable in patients. However, understanding the mechanisms underlying resistance to sunitinib remains incomplete. In order to decipher underlying drug-induced resistance mechanisms and identify potential targets to overcome sunitinib resistance in ccRCC, we developed a unique ccRCC xenograft model that mimicked clinical resistance to sunitinib. Methods: Untreated and sunitinib-treated Balb/C mice xenografted with RENCA cells were monitored for tumor growth. Sunitinib (40 mg/kg/day) administered 5 days/7 initially inhibited growth of xenografts, but tumors escaped after 6 weeks of continuous therapy. These sunitinib-induced resistant tumors were then removed and re-implanted to naïve Balb/C mice where re-implanted tumors exhibited immediately an aggressive phenotype. Re-implanted sunitinib-resistant tumors remained refractory to further treatment with sunitinib but responded to treatment with sorafenib and rapamycine, mimicking a strategy and tumor response that is often observed in the clinical setting. Transcriptomic and proteomic analyses of untreated, sunitinib-responsive and sunitinib-resistant tumors were performed, as well as evaluations of microvessel densities and host circulating angiogenic cells. Results: The aggressive phenotype of re-implanted sunitinib-resistant tumors suggested that the drug-induced acquired resistance was of intrinsic nature. However, transcriptomic analyses showed no differences in gene expression levels between untreated, sunitinib-responsive and sunitinib-resistant tumors. Proteomic analyses of tumors and serum samples are ongoing, as well as thorough analyses of the different angiogenic cellular compartments underlying host microenvironment responses. Conclusion: We have established a unique xenograft ccRCC model that mimicks clinical resistance to sunitinib. Our results show that while sunitinib-induced resistance is apparently intrinsic, tumor and host microenvironment are most likely critical mediators of resistance. 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 1377. doi:1538-7445.AM2012-1377