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Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance.

Abstract : Despite recent advances in the treatment of colorectal cancer (CRC), tumor resistance is a frequent cause of chemotherapy failure. Therefore, new treatment options are needed to improve survival of patients with irinotecan-refractory CRCs, 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. 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. We have shown that sorafenib improved the antitumoral 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. Moreover, we found that sorafenib improved the efficacy of irinotecan by inhibiting the irinotecan-mediated p38 and ERK activation. In 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 CRC, particularly in KRAS-mutated tumors.
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https://www.hal.inserm.fr/inserm-00861055
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Submitted on : Tuesday, August 12, 2014 - 4:51:27 PM
Last modification on : Friday, June 12, 2020 - 4:58:20 PM
Long-term archiving on: : Monday, November 17, 2014 - 3:57:54 PM

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Thibault Mazard, Annick Causse, Joelle Simony, Wilhem Leconet, Nadia Vezzio-Vie, et al.. Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.: Sorafenib inhibits ABCG2 and overcome irinotecan resistance.. Molecular Cancer Therapeutics, American Association for Cancer Research, 2013, 12 (10), pp.2121-34. ⟨10.1158/1535-7163.MCT-12-0966⟩. ⟨inserm-00861055⟩

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