Volume 107, Issue 1 p. 227-237
Article

Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1

Mingqing Chen

Mingqing Chen

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

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Claudia Neul

Claudia Neul

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

University of Tübingen, Tübingen, Germany

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Elke Schaeffeler

Elke Schaeffeler

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

University of Tübingen, Tübingen, Germany

Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany

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Franziska Frisch

Franziska Frisch

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

University of Tübingen, Tübingen, Germany

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Stefan Winter

Stefan Winter

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

University of Tübingen, Tübingen, Germany

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Matthias Schwab

Matthias Schwab

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany

Departments of Clinical Pharmacology, Pharmacy, and Biochemistry, University of Tübingen, Tübingen, Germany

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Hermann Koepsell

Hermann Koepsell

Institute of Anatomy and Cell Biology and Department of Molecular Plant Physiology and Biophysics, University of Würzburg, Würzburg, Germany

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Shuiying Hu

Shuiying Hu

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

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Stefan Laufer

Stefan Laufer

Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany

Department of Pharmaceutical and Medicinal Chemistry, University of Tübingen, Tübingen, Germany

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Sharyn D. Baker

Sharyn D. Baker

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

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Alex Sparreboom

Alex Sparreboom

Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA

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Anne T. Nies

Corresponding Author

Anne T. Nies

Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany

University of Tübingen, Tübingen, Germany

Cluster of Excellence iFIT (EXC2180) "Image-guided and Functionally Instructed Tumor Therapies", University of Tübingen, Tübingen, Germany

Correspondence: Anne T. Nies ([email protected])Search for more papers by this author
First published: 27 July 2019
Citations: 23
Alex Sparreboom and Anne T. Nies contributed equally to this work.

Abstract

Systemic therapy of advanced hepatocellular carcinoma (HCC) with the small-molecule multikinase inhibitor sorafenib is associated with large interindividual pharmacokinetic variability and unpredictable side effects potentially requiring dose reduction or treatment termination. Organic cation transporter (OCT1; gene SLC22A1) has been proposed as a 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-independent cellular sorafenib uptake indicating that OCT1 is apparently not a valid biomarker of sorafenib response in HCC.

Conflict of Interest

The authors declared no competing interests for this work.