The lack of the organic cation transporter OCT1 at the plasma membrane of tumor cells precludes a positive response to sorafenib in patients with hepatocellular carcinoma
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Andreas Geier1, Rocio I.R. Macias2, Dominik Bettinger3, Johannes Weiss1, Heike Bantel4, Daniel Jahn1, Ruba Al-Abdulla2, Jose J.G. Marin2
1Division of Hepatology, Department of Medicine II, University Hospital Würzburg, Würzburg, Germany
2Experimental Hepatology and Drug Targeting, CIBERehd, IBSAL, University of Salamanca, Salamanca, Spain
3Department of Medicine II, University Hospital Freiburg, Freiburg, Germany
4Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany
Andreas Geier, email: [email protected]
Keywords: organic cation transporter, chemoresistance, hepatocellular carcinoma, tyrosine-kinase inhibitor, sorafenib
Received: August 31, 2016 Accepted: January 06, 2017 Published: February 02, 2017
Background: Sorafenib is the drug of choice in the treatment of advanced hepatocellular carcinoma (HCC). Beneficial effects are limited by mechanisms of chemoresistance, which include downregulation and/or impaired function of plasma membrane transporters accounting for drug uptake. The organic cation transporter 1 (OCT1) plays a major role in sorafenib uptake and decreased expression in HCC has been associated with poorer response.
Methods: The multicenter retrospective TRANSFER study involved tumor biopsies from 39 patients with advanced HCC and sorafenib therapy for ≥4 wk. Endpoint was the relationship between clinicopathological features and immunohistological result. Immunostaining was performed using specific primary anti-OCT1-head and anti-OCT1-tail antibodies. Tumors were classified according to a simplified staining score as absent, weak, moderate or strong, taking into account the localization of the staining at the plasma membrane as positive or negative.
Results: Results confirmed OCT1 downregulation in half of the cases investigated (10% absent, 38% weak). However, only one third of tumors expressing OCT1 displayed plasma membrane location (15% vs. 36% cytosolic expression). When comparing HCC with and without OCT1 expression, no different sorafenib response was found. When tumors expressing OCT1 at the plasma membrane were considered separately, a marked longer survival was found (Log Rank p<0.001). No association between OCT1 expression at the plasma membrane with tumor stage, previous treatment with TACE or radiological response was seen.
In conclusion, these results indicate that the presence of OCT1 at the plasma membrane, rather than its expression levels, is related to better outcome of HCC patients treated with sorafenib.
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