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Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification

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Summary

Tivantinib has been described as a selective inhibitor of c-Met and is being studied in various types of cancer. In this study, we evaluated the effects of tivantinib on the suppression of gastric cancer (GC) cell migration and apoptosis. We also examined the mechanism of action of tivantinib by oncogenic pathway analysis. We applied an RNA-sequencing approach in 34 GC patients to identify oncogenes that are differentially expressed in GC tissues. To examine the inhibitory effect of tivantinib on GC cells, we conducted apoptosis analysis using an annexin V-APC/PI apoptosis detection kit and trans-well migration assay with human GC cell lines. For oncogenic pathway analysis, Western blot and quantitative real-time PCR analysis were used to detect the expression of proteins and genes before and after tivantinib exposure. In the RNA-sequencing analysis of 34 GC patients, c-Met and VEGFA genes were expressed and positively correlated with each other. Cell migration and apoptosis analysis demonstrated that tivantinib induced the best inhibition effect in SNU620, MKN45 (carries VEGFB mutation), AGS, and MKN28 cells, but not in KATO III (carries VEGFB and VEGFC mutations) cells. Oncogenic pathway analysis showed that tivantinib, in addition to c-Met signaling pathway inhibition, also inhibits VEGF signaling and MYC expression in VEGFA-expressing GC cells. We found that tivantinib has anti-cancer activity not only in GC cells overexpressing c-Met but also in non-c-Met GC cells by inhibition of the VEGF signaling pathway.

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Acknowledgements

We would like to thank the patients and all of the investigators who participated in these studies. The authors were fully responsible for all content and editorial decisions, and were involved at all stages of manuscript development.

Funding

This research was supported by the National R&D Program for Cancer Control, Ministry of Health and Welfare (HA17C0054), the National Research Foundation of Korea grant funded by the Korean Ministry of Science and ICT (NRF-2017R1A2B4005055), the Ministry of Food and Drug Safety of Korea (awarded in 2018, 18183MFDS491), and the Hallym University Research Fund. These funding sources had no role in the design of the study, writing of the manuscript, or the collection, analysis and interpretation of the data.

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Author notes

  1. Bum Jun Kim, Yoo Jin Kim and Sung-Hwa Sohn contributed equally to this work.

Authors and Affiliations

  1. Division of Internal Medicine, National Army Capital Hospital, The Armed Forces Medical Command, Sungnam, 13574, Republic of Korea

    Bum Jun Kim

  2. Hallym Translational Research Institute, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea

    Yoo Jin Kim, Sung-Hwa Sohn, Bohyun Kim, Hee Jung Sul & Dae Young Zang

  3. Division of Hematology-Oncology, Department of Internal Medicine, Hallym University Medical Center, Hallym University College of Medicine, Anyang-si, Gyeonggi-do, 14068, Republic of Korea

    Hyeong Su Kim & Dae Young Zang

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  1. Bum Jun Kim
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by BJ Kim, YJ Kim and S Sohn. All authors participated in writing the first draft of the manuscript and commented on subsequent versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Dae Young Zang.

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The authors have no conflicts of interest to disclose.

Ethical approval

The use of human tissues in this study was approved by the Ethics Committee of Hallym University Sacred Heart Hospital.

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Informed consent was obtained from all individual participants included in the study.

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Bum Jun Kim, Yoo Jin Kim and Sung-Hwa Sohn should be considered as co-first authors.

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Kim, B.J., Kim, Y.J., Sohn, SH. et al. Tivantinib inhibits the VEGF signaling pathway and induces apoptosis in gastric cancer cells with c-MET or VEGFA amplification. Invest New Drugs 38, 1633–1640 (2020). https://doi.org/10.1007/s10637-020-00940-3

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  • DOI: https://doi.org/10.1007/s10637-020-00940-3

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