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Overexpression of ABCB1 confers resistance to FLT3 inhibitor FN-1501 in cancer cells: in vitro and in vivo characterization

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机构： [1]Department of Thyroid and Breast Surgery, Shenzhen Hospital of Southern Medical University No. 1333 Xinhu Road, Baoan, Shenzhen 510000, Guangdong, China. [2]Dalton Cardiovascular Research Center, Department of Medical Pharmacology and Physiology, University of Missouri, School of Medicine 134 Research Park Dr, Columbia, MO 65211, USA. [3]Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University Queens, NY 11439, USA. [4]Department of Cancer Biology, University of Toledo College of Medicine and Life Sciences Toledo, OH 43606, USA. [5]Department of Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University No. 1333 Xinhu Road, Baoan, Shenzhen 510000, Guangdong, China. [6]School of Life Science and Technology, Weifang Medical University No. 7166 Baotong Street, Weicheng, Weifang 261053, Shandong, China. [7]School of Traditional Chinese Medicine, Southern Medical University No. 1023 Satai South Road, Baiyun, Guangzhou 510000, Guangdong, China.

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关键词： FN-1501 FLT3 inhibitor multidrug resistance ABC transporter ABCB1

摘要：

FN-1501 is a potent FLT3 inhibitor with antitumor activity. A phase 1 trial of FN-1501 monotherapy in patients with advanced solid tumors and R/R AML is in progress. Since one of the primary causes of multidrug resistance (MDR) is the overexpression of ATP-binding cassette superfamily B member 1 (ABCB1), the objective of this study was to investigate the potential relationship between FN-1501 and the ABCB1 transporter. We found ABCB1 overexpressing-cancer cells conferred FN-1501 resistance, which could be reversed by an ABCB1 inhibitor. Molecular docking study revealed that FN-1501 docked the ligand binding site with an affinity score of -9.77 kcal/mol, denoting a strong interaction between FN-1501 and ABCB1. Additionally, the ABCB1 ATPase assay indicated that FN-1501 could significantly stimulate ABCB1 ATPase activity. Furthermore, we observed a similar trend of ABCB1-facilated FN-1501 resistance in tumor-bearing mice model. In sum, we demonstrate that FN-1501 is a substrate of ABCB1 transporter from both in vivo and in vitro studies. Therefore, our findings provide new insight on the mechanism of chemoresistance due to ABCB1 overexpression.AJCR Copyright © 2023.

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出版当年[2022]版：

大类 | 3 区医学

小类 | 3 区肿瘤学

最新[2025]版：

大类 | 3 区医学

小类 | 4 区肿瘤学

第一作者：

第一作者机构： [1]Department of Thyroid and Breast Surgery, Shenzhen Hospital of Southern Medical University No. 1333 Xinhu Road, Baoan, Shenzhen 510000, Guangdong, China.

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通讯作者：

通讯机构： [5]Department of Traditional Chinese Medicine, Shenzhen Hospital of Southern Medical University No. 1333 Xinhu Road, Baoan, Shenzhen 510000, Guangdong, China. [7]School of Traditional Chinese Medicine, Southern Medical University No. 1023 Satai South Road, Baiyun, Guangzhou 510000, Guangdong, China.

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