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Open AccessArticle

Tivantinib, A c-Met Inhibitor in Clinical Trials, Is Susceptible to ABCG2-Mediated Drug Resistance

1
Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA
2
College of Chemical Engineering, Nanjing Forestry University, Nanjing 210037, China
3
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD 20892, USA
*
Authors to whom correspondence should be addressed.
Cancers 2020, 12(1), 186; https://doi.org/10.3390/cancers12010186
Received: 16 December 2019 / Revised: 7 January 2020 / Accepted: 9 January 2020 / Published: 12 January 2020
Tivantinib, also known as ARQ-197, is a potent non-ATP competitive selective c-Met inhibitor currently under phase 3 clinical trial evaluation for liver and lung cancers. In this study, we explored factors that may lead to tivantinib resistance, especially in regards to its interaction with ATP-binding cassette super-family G member 2 (ABCG2). ABCG2 is one of the most important members of the ATP-binding cassette (ABC) transporter family, a group of membrane proteins that play a critical role in mediating multidrug resistance (MDR) in a variety of cancers, including those of the liver and lung. Tivantinib received a high score in docking analysis, indicating a strong interaction between tivantinib and ABCG2, and an ATPase assay indicated that tivantinib stimulated ABCG2 ATPase activity in a concentration-dependent manner. An MTT assay showed that ABCG2 overexpression significantly desensitized both the cancer cells and ABCG2 transfected-HEK293 cells to tivantinib and that this drug resistance can be reversed by ABCG2 inhibitors. Furthermore, tivantinib upregulated the protein expression of ABCG2 without altering the cell surface localization of ABCG2, leading to increased resistance to substrate drugs, such as mitoxantrone. Altogether, these data demonstrate that tivantinib is a substrate of ABCG2, and, therefore, ABCG2 overexpression may decrease its therapeutic effect. Our study provides evidence that the overexpression of ABCG2 should be monitored in clinical settings as an important risk factor for tivantinib drug resistance. View Full-Text
Keywords: ATP-binding cassette (ABC) transporter; tivantinib; ARQ-197; ABCG2; drug transport; multidrug resistance (MDR) ATP-binding cassette (ABC) transporter; tivantinib; ARQ-197; ABCG2; drug transport; multidrug resistance (MDR)
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Wu, Z.-X.; Yang, Y.; Teng, Q.-X.; Wang, J.-Q.; Lei, Z.-N.; Wang, J.-Q.; Lusvarghi, S.; Ambudkar, S.V.; Yang, D.-H.; Chen, Z.-S. Tivantinib, A c-Met Inhibitor in Clinical Trials, Is Susceptible to ABCG2-Mediated Drug Resistance. Cancers 2020, 12, 186.

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