肝细胞癌（HCC）中有机阳离子转运体1（OCT1）功能受损与索拉非尼不良反应相关。然而，一些缺乏HCC细胞质膜（PM）上OCT1的患者仍然对索拉非尼有反应，这表明另一种转运体可能有助于摄取这种药物。本研究的目的是调查OCT3是否可以有助于索拉非尼和其他酪氨酸激酶抑制剂（TKI）的摄取，并确定OCT3的测定是否能预测HCC对索拉非尼的反应。使用过表达OCT3的细胞确定这种载体对索拉非尼的转运能力。在TRANSFER研究中获取的HCC样本中进行OCT3的免疫染色。根据染色强度和OCT3阳性细胞数目，将肿瘤分为缺失、弱阳性、中度阳性和强阳性的OCT3表达，并根据PM染色的存在与否进行分类。功能性体外研究显示OCT3也能介导索拉非尼的摄取。其他TKI（如雷格菲尼、力伐替尼和卡泊替尼）也可以与这种转运体发生相互作用。体外研究表明，OCT3在HCC的表达比OCT1更好保留。在HCC样本中，OCT3在癌细胞的PM上表达，并且在26%的肿瘤中检测到其存在，与接受索拉非尼治疗的患者的临床结果良好相关。总之，通过免疫组化分析肿瘤细胞PM中的OCT3可以帮助预测HCC患者对索拉非尼甚至其他TKI的反应。版权所有© 2023作者。由Elsevier Inc.发表并保留所有权利。

Impaired function of organic cation transporter 1 (OCT1) in hepatocellular carcinoma (HCC) has been associated with unsatisfactory response to sorafenib. However, some patients lacking OCT1 at the plasma membrane (PM) of HCC cells still responded to sorafenib, suggesting that another transporter may contribute to take up this drug. The aim of this study was to investigate whether OCT3 could contribute to the uptake of sorafenib and other tyrosine kinase inhibitors (TKIs) and whether OCT3 determination can predict HCC response to sorafenib. Cells overexpressing OCT3 were used to determine the ability of this carrier to transport sorafenib. Immunostaining of OCT3 was performed in HCC samples obtained in the TRANSFER study. Considering the intensity of staining and the number of OCT3-positive cells, tumors were classified as having absent, weak, moderate, or strong OCT3 expression and were also categorized according to the presence or absence of PM staining. Functional in vitro studies revealed that OCT3 is also able to mediate sorafenib uptake. Other TKIs, such as regorafenib, lenvatinib, and cabozantinib can also interact with this transporter. In silico studies suggested that the expression of OCT3 is better preserved in HCC than that of OCT1. In HCC samples, OCT3 was expressed at the PM of cancer cells, and its presence, detected in 26% of tumors, was associated with better outcomes in patients treated with sorafenib. In conclusion, analysis by immunohistochemistry of OCT3 in the PM of tumor cells may help to predict the response of HCC patients to sorafenib and potentially to other TKIs.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.