Abstract
Abstract Background: Despite recent advances in the treatment of colorectal cancer, tumor resistance is a frequent cause of chemotherapy failure. Thus, new treatment options are needed to improve survival of patients with irinotecan-refractory colorectal cancers, particularly those bearing KRAS mutations that preclude the use of anti-EGFR therapies. In this study, we investigated whether sorafenib could reverse irinotecan resistance, thereby enhancing the therapeutic efficacy of routinely used irinotecan-based chemotherapy. Materials and methods: We used both in vitro (the HCT116, SW48, SW620 and HT29 colon adenocarcinoma cell lines and four SN-38 resistant HCT-116 and SW48 clones) and in vivo models (nude mice xenografted with SN-38 resistant HCT116 cells) to test the efficacy of sorafenib alone or in combination with irinotecan, or its active metabolite SN-38. Results: Sorafenib improved the anti-tumoral activity of irinotecan in vitro, in both parental and SN-38 resistant colon adenocarcinoma cell lines independently of their KRAS status, as well as in vivo, in xenografted mice. By inhibiting the drug-efflux pump ABCG2, sorafenib favors irinotecan intracellular accumulation and enhances its toxicity. Conclusion: Our results show that sorafenib can suppress resistance to irinotecan and suggest that sorafenib could be used to overcome resistance to irinotecan-based chemotherapies in colorectal cancer, particularly in KRAS mutated tumors. Citation Format: Thibault Mazard, Annick Causse, Joelle Simony, Wilhem Leconet, Marta Jarlier, Marc Ychou, Maguy Del Rio, Pierre Martineau, Bruno Robert, Céline Gongora. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 975. doi:10.1158/1538-7445.AM2013-975
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