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Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer

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Abstract

Purpose

Epigenetic dysregulation is a common characteristic of cancers, including gastric cancer (GC), and contributes to cancer development and progression. Although the efficacy of BET (an epigenetic regulator) inhibition has been demonstrated in various cancer types, predictive genetic markers of its efficacy in GC are currently lacking. Therefore, we aimed to identify markers that predict the response of BET inhibition in GC and, suggest an effective treatment regimen through combined therapy.

Methods

The effect of BET inhibition was evaluated using iBET-151, a small-molecule inhibitor of BET proteins, in a large panel (n = 49) of GC cell lines and xenograft mouse models. Comprehensive genetic information was used to identify cell lines sensitive to iBET-151. Flow cytometry, Western blotting, and colony-formation and migration assays were used to evaluate the effects of iBET-151 and/or paclitaxel. The synergistic effect of iBET-151 and paclitaxel was evaluated using an organoid model.

Results

We found that iBET-151 showed a modest growth-inhibitory effect in GC cells (73%, 36/49). iBET-151 inhibited tumorigenicity in vitro and significantly promoted cell cycle arrest and apoptosis. Based on comprehensive genetic information analysis in relation to BET family expression, we found that BRD4 was highly expressed in the iBET-151-sensitive cell lines. We also identified WNT5B and IRS2 as potential biomarkers that are predictive for sensitivity to iBET-151. In GC xenograft model mice, iBET-151 significantly decreased tumor volumes and Ki-67 and BRD4 expression. Combination treatment showed that iBET-151 increased the sensitivity of GC cells to paclitaxel in approximately 70% of the cell lines (34/49) tested. iBET-151 plus paclitaxel significantly promoted cell cycle arrest and apoptosis and suppressed c-Myc, Bcl-2 and Bcl-xL expression. In GC organoids, iBET-151 and paclitaxel showed a synergistic effect.

Conclusions

Collectively, our data suggest that iBET-151 is a potential therapeutic agent for GC, especially in combination with paclitaxel, and that WNT5B and IRS2 may predict iBET-151 sensitivity.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

BET :

Bromodomain and Extra-terminal

BRD4 :

Bromodomain-containing protein 4

CI :

Combination index

CIN :

Chromosomal instability

EBV :

Epstein–Barr virus

GC :

Gastric cancer

GS :

Genomic stability

IC50 :

Half-maximal inhibitory concentration

MSI-H :

High microsatellite instability

SD :

standard deviation

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Acknowledgments

We thank all members of the CMRC lab for discussion. We thank Hyun Jeong Kim, Ka Ram Ahn, Chanmi Lee, Sarah Lee and Sarah Park for advice and comments on the article. We also thank Yoonseok Yu (CBSBio. Com, Korea) for bioinformatics support and GlaxoSmithKline Biologicals SA. for providing iBET-151. This work was supported by a National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT)(2020R1A2B5B02001452) and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea(HA15C0005).

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Authors and Affiliations

  1. Songdang Institute for Cancer Research, Yonsei University College of Medicine, Seoul, Republic of Korea

    Sun Kyoung Kang, Hyun Joo Bae, Woo Sun Kwon, Tae Soo Kim, Kyoo Hyun Kim, Sejung Park, Seo Young Yu, Jihyun Hwang, Juin Park, Hyun Cheol Chung & Sun Young Rha

  2. MD Biolab Co., Ltd, Seoul, Republic of Korea

    Sun Kyoung Kang

  3. Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea

    Hyun Joo Bae, Woo Sun Kwon, Tae Soo Kim, Kyoo Hyun Kim, Sejung Park, Seo Young Yu, Jihyun Hwang, Juin Park, Hyun Cheol Chung & Sun Young Rha

  4. Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Republic of Korea

    Hyun Joo Bae, Seo Young Yu, Jihyun Hwang, Hyun Cheol Chung & Sun Young Rha

  5. Department of Biostatistics and Computing, Yonsei University College of Medicine, Seoul, Republic of Korea

    Sejung Park

  6. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul, 03722, Republic of Korea

    Hyun Cheol Chung & Sun Young Rha

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Kang, S.K., Bae, H.J., Kwon, W.S. et al. Inhibition of the bromodomain and extra-terminal family of epigenetic regulators as a promising therapeutic approach for gastric cancer. Cell Oncol. 44, 1387–1403 (2021). https://doi.org/10.1007/s13402-021-00647-4

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