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 irinotecanmediated 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.

ERK activation and autophagy impairment are central mediators of irinotecan-induced steatohepatitis

“…Previous experimental studies indicated the potential of this multityrosine kinase inhibitor to augment the antitumour efficacy of irinotecan in hepatocellular carcinoma cells20 21 and to overcome irinotecan resistance in colorectal cancer cells in mice 27. Furthermore, the Web-based register ClinicalTrials.gov (https://clinicaltrials.gov) specifies ongoing and recently closed studies, respectively, analysing the safety and efficacy of a combined therapy with irinotecan and sorafenib versus irinotecan or sorafenib monotherapy in patients with colorectal neoplasms or paediatric solid tumours.…”

Sorafenib and irinotecan (NEXIRI) as second- or later-line treatment for patients with metastatic colorectal cancer and KRAS-mutated tumours: a multicentre Phase I/II trial

“…Other studies have shown that multi-tyrosine kinase inhibitors such as sorafenib may also reverse irinotecan resistance (Mross et al , 2007; Azad et al , 2013). Indeed, sorafenib has been identified both in vitro and in vivo as an inhibitor of the drug-efflux pump ABCG2, favouring irinotecan intracellular accumulation thereby enhancing its toxicity (Mazard et al , 2013). This chemosensitizing property previously described by Wei et al (2012) has also been ascribed to the inhibition of the irinotecan-mediated p38 and ERK activation (Mazard et al , 2013).…”

“…In humans, only a Phase I trial showed the feasibility of combining a weekly schedule of irinotecan 125 mg m − 2 (D1,8,15,22 D1=D42) and a fixed dose of sorafenib 400 mg twice daily in 34 patients with solid tumours (23 of whom had colorectal cancer) (Mross et al , 2007). However, preclinical promising results had already been gathered on the synergistic effect of this combination particularly in KRAS -mutated tumours (personal communication at the time) and were recently published (Mazard et al , 2013). …”

ABCG2/BCRP: Specific and Nonspecific Modulators

“…Mutations of the EGFR are correlated with tumor proliferation. Inhibition of EGFR by smallmolecule inhibitors, such as gefitinib (151), pelitinib (152), neratinib (153), vandetanib (154), and telatinib (155), is therefore a promising therapeutic option. 2 Gefitinib (151, "Iressa," ZD1839, Fig.…”