No abstract

Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small molecule multikinase inhibitor sorafenib is associated with large inter-individual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter OCT1 (gene SLC22A1) has been proposed as clinical biomarker of HCC response. Because proof is lacking that OCT1 transports sorafenib, we used a combinatorial approach to define how OCT1 contributes to sorafenib transport. Overexpression of functional OCT1 protein in Xenopus laevis oocytes and mammalian cell lines did not facilitate sorafenib transport. Otherwise, sorafenib considerably accumulated in liver cancer cell lines despite negligible OCT1 mRNA and protein levels. Sorafenib pharmacokinetics was independent of OCT1 genotype in mice. Finally, SLC22A1 mRNA expression was significantly reduced by DNA methylation in The Cancer Genome Atlas HCC cohort. These results clearly demonstrate OCT1-

The multikinase inhibitor sorafenib is approved for the treatment of advanced clear-cell renal and hepatocellular carcinomas, yet, patients’ survival is prolonged for only several months (Wilhelm et al., Mol Cancer Ther 2008). The understanding of this poor efficacy remains incomplete. One reason for treatment failure may be the high interindividual variability in pharmacokinetics of the orally-given sorafenib. Membrane transporters may contribute to pharmacokinetics of sorafenib and its metabolites as recently reported for the hepatic solute carrier (SLC) organic anion transporter family member 1B1 (OATP1B1) and OATP1B3 (Zimmerman et al, Clin Cancer Res 2013). In contrast, the role of organic cation transporter 1 (OCT1), which is also a major hepatic uptake transporter (Nies et al, Handb Exp Pharmacol 2011), for cellular uptake of sorafenib is controversial (Hu et al, Clin Cancer Res 2009; Swift et al, Drug Metab Dispos 2013; Herraez et al, Hepatology 2013). We therefore sought to comprehensively elucidate the impact of OCT1 on cellular sorafenib uptake by using a combination of different in vitro cell culture models and in vivo approaches involving experiments with Oct1 knockout (-/-) mice. Firstly, we analyzed cellular accumulation of radiolabeled sorafenib by the mammalian cell line HEK293 stably expressing OCT1. Despite overexpression of a functional OCT1 transporter, cellular uptake of neither sorafenib nor its active metabolite sorafenib N-oxide was increased. Next, we studied sorafenib and sorafenib N-oxide pharmacokinetics in mice with a homozygous genetic deletion of the Oct1 transporter. The deficiency of Oct1 had no influence on plasma and hepatic sorafenib and sorafenib N-oxide concentrations. Finally, we investigated sorafenib transport into the human hepatocellular carcinoma cell lines HepG2 and HuH7. Although neither OCT1 mRNA nor protein was detected, a considerable cellular accumulation of sorafenib was observed in both cell lines. Expression profiling of a panel of 55 relevant SLC drug uptake transporters identified several potential novel candidates mediating sorafenib accumulation. We conclude from these findings that cellular uptake of sorafenib and sorafenib N-oxide is independent of OCT1 and that other, as yet unidentified, transport mechanisms are responsible for cellular sorafenib uptake. Supported by the Robert Bosch Foundation, Stuttgart, Germany and the ICEPHA Grant Tübingen-Stuttgart, Germany. Citation Format: Claudia Neul, Sharyn D. Baker, Alex Sparreboom, Elke Schaeffeler, Stefan Laufer, Matthias Schwab, Anne T. Nies. Evaluation of organic cation transporter 1 (OCT1, SLC22A1) as transporter for sorafenib. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 257.