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.
Highlights
Receptor tyrosine kinases (RTKs) play a critical role in regulating cellular function
We report that ATP-binding cassette super-family G member 2 (ABCG2) overexpression can confer resistance to tivantinib, which can be reversed by ABCG2 inhibitors
The cell lines used in this study were NSCLC NCI-H460 and its drug-selected subline, NCI-H460/MX20, which overexpresses wild-type (WT) ABCG2 and colon cancer cell line S1, as well as its drug-selected subline, S1-M1-80, which overexpresses R482G mutant ABCG2
Summary
Receptor tyrosine kinases (RTKs) play a critical role in regulating cellular function. Strong evidence has shown that prolonged activation of c-Met is linked to tumor growth or progression. Some tyrosine kinase inhibitors (TKIs) targeting c-Met have been developed and have shown promising therapeutic effects. Tepotinib is under a phase 2 clinical evaluation and showed a promising effect against liver cancer (NCT02115373) and non-small cell lung cancer (NSCLC, NCT02864992) [3]. Glesatinib is another drug in a phase 2 clinical trial (NCT02954991) that investigates its therapeutic effect of NSCLC [4]. Capmatinib was shown to be effective against NSCLC [5]
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