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

Authors
 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 
Citation
 CELLULAR ONCOLOGY, Vol.44(6) : 1387-1403, 2021-12 
Journal Title
CELLULAR ONCOLOGY
ISSN
 2211-3428 
Issue Date
2021-12
MeSH
Animals ; Biomarkers, Tumor / metabolism ; Cell Adhesion ; Cell Cycle Checkpoints ; Cell Cycle Proteins / metabolism ; Cell Death ; Cell Line, Tumor ; Cell Proliferation ; Drug Synergism ; Epigenesis, Genetic* / drug effects ; Female ; Mice, Inbred BALB C ; Mice, Nude ; Molecular Targeted Therapy ; Organoids / drug effects ; Organoids / pathology ; Paclitaxel / pharmacology ; Paclitaxel / therapeutic use ; Stomach Neoplasms / drug therapy* ; Stomach Neoplasms / genetics* ; Transcription Factors / antagonists & inhibitors* ; Transcription Factors / metabolism ; Xenograft Model Antitumor Assays
Keywords
BET inhibitor ; BET protein ; Combination therapy ; Epigenetic regulation ; GC organoid ; Gastric cancer ; Paclitaxel
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.
Full Text
https://link.springer.com/article/10.1007/s13402-021-00647-4
DOI
10.1007/s13402-021-00647-4
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Woo Sun(권우선) ORCID logo https://orcid.org/0000-0003-0268-5624
Rha, Sun Young(라선영) ORCID logo https://orcid.org/0000-0002-2512-4531
Chung, Hyun Cheol(정현철) ORCID logo https://orcid.org/0000-0002-0920-9471
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/188182
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