Résumé
Despite recent advances in the treatment of colon cancer, tumor resistance is a frequent cause of chemotherapy failure. In the last decade, several studies have shown that cetuximab, an anti-EGFR monoclonal antibody, can overcome acquired resistance to irinotecan chemotherapy, but only in KRAS non mutant tumors. Thus, new treatment options are needed to improve survival in patients with irinotecan refractory and KRAS mutated colorectal cancer. In this study, we examined if treatment with sorafenib, a potent inhibitor of Raf kinase and VEGF receptor, could reverse the resistant phenotype in tumor, thereby enhancing the therapeutic efficacy of currently used irinotecan treatment. We used both in vitro and in vivo models to test the efficacy of sorafenib either as a single agent or in combination with irinotecan. We have first tested these different combinations on seven colorectal cancer cell lines displaying different molecular characteristics (mutated or not for KRAS, BRAF, p53 and PIK3CA). We have shown that sorafenib, as a single agent, showed antitumor properties and the effects were more pronounced when it was used in combination with the active metabolite of irinotecan, SN38. Then we have tested these treatments on SN38-resistant clones derived from the colon adenocarcinoma HCT-116 (KRAS mut) and SW48 (KRAS WT) cell lines, that show various levels (6 to 60 fold) of resistance to SN-38 as compared to the corresponding parental cells. Sorafenib has improved the anti-tumoral activity of SN-38 on all the SN38 resistant clones in vitro. Moreover, sorafenib sensitized tumor cells derived from both SN38-sensitive and -resistant HCT116 cells to irinotecan treatment in xenograft models. Signalling pathways involved in this effect have been identified on xenografts using the proteome profiler array. Altogether, our results show for the first time that sorafenib can inhibit 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: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1902. doi:1538-7445.AM2012-1902