title: Sorafenib overcomes irinotecan resistance in colorectal cancer by inhibiting the ABCG2 drug-efflux pump.
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.
authors: Corresponding Author: Dr. Céline Gongora, IRCM INSERM U896, 208, rue des Apothicaires, 34298 Montpellier, France. celine.gongora@inserm.fr.
authors: Thibault
authors: T
authors: Mazard
authors: Annick
authors: A
authors: Causse
authors: Joelle
authors: J
authors: Simony
authors: Wilhem
authors: W
authors: Leconet
authors: Nadia
authors: N
authors: Vezzio-Vie
authors: Adeline
authors: A
authors: Torro
authors: Marta
authors: M
authors: Jarlier
authors: Alexandre
authors: A
authors: Evrard
authors: Maguy
authors: M
authors: Del Rio
authors: Eric
authors: E
authors: Assenat
authors: Pierre
authors: P
authors: Martineau
authors: Marc
authors: M
authors: Ychou
authors: Bruno
authors: B
authors: Robert
authors: Celine
authors: C
authors: Gongora
mesh_terms: D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D066246:ErbB Receptors; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D009363:Neoplasm Proteins / Q000235:genetics*; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D000077157:Sorafenib; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: C116614:ABCG2 protein, human; D000070997:ATP Binding Cassette Transporter, Subfamily G, Member 2; D018528:ATP-Binding Cassette Transporters; C117307:KRAS protein, human; D009363:Neoplasm Proteins; D010671:Phenylurea Compounds; D011518:Proto-Oncogene Proteins; D009536:Niacinamide; D000077146:Irinotecan; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002166:Camptothecin