XB-ART-56158Clin Pharmacol Ther January 1, 2020; 107 (1): 227-237.
Sorafenib Activity and Disposition in Liver Cancer Does Not Depend on Organic Cation Transporter 1.
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.
PubMed ID: 31350763
PMC ID: PMC6925656
Article link: Clin Pharmacol Ther
Genes referenced: pou2f1
GO keywords: DNA methylation
Disease Ontology terms: hepatocellular carcinoma
References [+] :
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