{"doi":"10.1158/1538-7445.am2012-1377","title":"Abstract 1377: Characterisation of mechanisms of resistance to sunitinib in a unique pre-clinical RCC model","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>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.</jats:p>\n               <jats:p>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</jats:p>","journal":"Cancer Research","year":2012,"id":652117,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":null,"is_data_producer":false,"deposit_databanks":null,"is_oa":false,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":null,"fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1700993,"name":"Amélie Barthélémy","orcid":null,"position":1,"is_corresponding":false},{"id":91584,"name":"Bernard Escudier","orcid":"0000-0002-4626-0479","position":2,"is_corresponding":false},{"id":1700994,"name":"Françoise Farace","orcid":null,"position":3,"is_corresponding":false},{"id":978871,"name":"Melissa Taylor","orcid":"0009-0006-3506-0902","position":0,"is_corresponding":false}],"reference_count":0,"raw_metadata":{"has_enrichment":true,"resolved":true,"title":"Abstract 1377: Characterisation of mechanisms of resistance to sunitinib in a unique pre-clinical RCC model","abstract":"<jats:title>Abstract</jats:title>\n               <jats:p>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.</jats:p>\n               <jats:p>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. 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