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

• Published in: Molecular cancer therapeutics 2013-10, Vol.12 (10), p.2121-34
• Main Authors: Mazard, Thibault, Causse, Annick, Simony, Joelle, Leconet, Wilhem, Vezzio-Vie, Nadia, Torro, Adeline, Jarlier, Marta, Evrard, Alexandre, del Rio, Maguy, Assenat, Eric, Martineau, Pierre, Ychou, Marc, Robert, Bruno, Gongora, Celine
• Format: Article
• Language: English
• Subjects: Animals; ATP-Binding Cassette Transporters; Biochemistry, Molecular Biology; Camptothecin; Cancer; Colorectal Neoplasms; Drug Resistance, Neoplasm; Drug Synergism; Gene Expression Regulation, Neoplastic; HCT116 Cells; Humans; Life Sciences; Mice; Neoplasm Proteins; Niacinamide; Pharmaceutical sciences; Phenylurea Compounds; Proto-Oncogene Proteins; ras Proteins; Receptor, Epidermal Growth Factor; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-12-0966

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.