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

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          Abstract

          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.

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          Most cited references38

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          Role of the breast cancer resistance protein (BCRP/ABCG2) in drug transport--an update.

          The human breast cancer resistance protein (BCRP, gene symbol ABCG2) is an ATP-binding cassette (ABC) efflux transporter. It was so named because it was initially cloned from a multidrug-resistant breast cancer cell line where it was found to confer resistance to chemotherapeutic agents such as mitoxantrone and topotecan. Since its discovery in 1998, the substrates of BCRP have been rapidly expanding to include not only therapeutic agents but also physiological substances such as estrone-3-sulfate, 17β-estradiol 17-(β-D-glucuronide) and uric acid. Likewise, at least hundreds of BCRP inhibitors have been identified. Among normal human tissues, BCRP is highly expressed on the apical membranes of the placental syncytiotrophoblasts, the intestinal epithelium, the liver hepatocytes, the endothelial cells of brain microvessels, and the renal proximal tubular cells, contributing to the absorption, distribution, and elimination of drugs and endogenous compounds as well as tissue protection against xenobiotic exposure. As a result, BCRP has now been recognized by the FDA to be one of the key drug transporters involved in clinically relevant drug disposition. We published a highly-accessed review article on BCRP in 2005, and much progress has been made since then. In this review, we provide an update of current knowledge on basic biochemistry and pharmacological functions of BCRP as well as its relevance to drug resistance and drug disposition.
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            Structural basis of small-molecule inhibition of human multidrug transporter ABCG2

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              Molecular mechanisms of drug resistance and its reversal in cancer.

              Chemotherapy is the main strategy for the treatment of cancer. However, the main problem limiting the success of chemotherapy is the development of multidrug resistance. The resistance can be intrinsic or acquired. The resistance phenotype is associated with the tumor cells that gain a cross-resistance to a large range of drugs that are structurally and functionally different. Multidrug resistance arises via many unrelated mechanisms, such as overexpression of energy-dependent efflux proteins, decrease in uptake of the agents, increase or alteration in drug targets, modification of cell cycle checkpoints, inactivation of the agents, compartmentalization of the agents, inhibition of apoptosis and aberrant bioactive sphingolipid metabolism. Exact elucidation of resistance mechanisms and molecular and biochemical approaches to overcome multidrug resistance have been a major goal in cancer research. This review comprises the mechanisms guiding multidrug resistance in cancer chemotherapy and also touches on approaches for reversing the resistance.
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                Author and article information

                Journal
                Cancers (Basel)
                Cancers (Basel)
                cancers
                Cancers
                MDPI
                2072-6694
                12 January 2020
                January 2020
                : 12
                : 1
                : 186
                Affiliations
                [1 ]Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, Queens, NY 11439, USA; zhuoxun.wu17@ 123456my.stjohns.edu (Z.-X.W.); yuqi.yang17@ 123456my.stjohns.edu (Y.Y.); qiuxu.teng15@ 123456my.stjohns.edu (Q.-X.T.); jingquan.wang16@ 123456my.stjohns.edu (J.-Q.W.); zining.lei14@ 123456my.stjohns.edu (Z.-N.L.); 18761687786@ 123456163.com (J.-Q.W.)
                [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; sabrinal@ 123456mail.nih.gov (S.L.); ambudkar@ 123456mail.nih.gov (S.V.A.)
                Author notes
                [* ]Correspondence: yangd1@ 123456stjohns.edu (D.-H.Y.); chenz@ 123456stjohns.edu (Z.-S.C.); Tel.: +1-718-990-6468 (D.-H.Y.); +1-718-990-1432 (Z.-S.C.); Fax: +1-718-990-1877 (D.-H.Y. & Z.-S.C.)
                Author information
                https://orcid.org/0000-0002-2639-4955
                https://orcid.org/0000-0002-8289-097X
                Article
                cancers-12-00186
                10.3390/cancers12010186
                7017082
                31940916
                6483a518-8c6d-48c3-8e14-ec2b2d2c7aaf
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 16 December 2019
                : 09 January 2020
                Categories
                Article

                atp-binding cassette (abc) transporter,tivantinib,arq-197,abcg2,drug transport,multidrug resistance (mdr)

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