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

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.

Mots clés

ABCG2 colorectal cancer irinotecan sorafenib

Domaines

Biochimie, Biologie Moléculaire Cancer Sciences pharmaceutiques

Fichier principal

Article.pdf (306.34 Ko)

Figure1.ppt (105.5 Ko)

Figure2.ppt (80 Ko)

Figure3.ppt (3.45 Mo)

Figure4.ppt (2.74 Mo)

Figure5.ppt (133 Ko)

Figure6.ppt (1.79 Mo)

Origine : Fichiers produits par l'(les) auteur(s)

Format : Autre

Yves Le Ster : Connectez-vous pour contacter le contributeur

https://inserm.hal.science/inserm-00861055

Soumis le : mardi 12 août 2014-16:51:27

Dernière modification le : jeudi 1 février 2024-14:20:59

Archivage à long terme le : lundi 17 novembre 2014-15:57:54

Dates et versions

inserm-00861055 , version 1 (12-08-2014)

Identifiants

HAL Id : inserm-00861055 , version 1
DOI : 10.1158/1535-7163.MCT-12-0966
PUBMED : 23960095

Citer

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, 2013, 12 (10), pp.2121-34. ⟨10.1158/1535-7163.MCT-12-0966⟩. ⟨inserm-00861055⟩

Exporter

BibTeX XML-TEI Dublin Core DC Terms EndNote DataCite

Collections

INSERM FNCLCC VALDAURELLE BS UNIV-MONTPELLIER IRCM ANR

523 Consultations

728 Téléchargements