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Bromodomain and extraterminal domain inhibition synergizes with WEE1-inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer

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Title: Bromodomain and extraterminal domain inhibition synergizes with WEE1-inhibitor AZD1775 effect by impairing nonhomologous end joining and enhancing DNA damage in nonsmall cell lung cancer
Authors: Takashima, Yuta Browse this author
Kikuchi, Eiki Browse this author →KAKEN DB
Kikuchi, Junko Browse this author
Suzuki, Motofumi Browse this author
Kikuchi, Hajime Browse this author
Maeda, Makie Browse this author
Shoji, Tetsuaki Browse this author
Furuta, Megumi Browse this author →KAKEN DB
Kinoshita, Ichiro Browse this author →KAKEN DB
Dosaka-Akita, Hirotoshi Browse this author →KAKEN DB
Sakakibara-Konishi, Jun Browse this author →KAKEN DB
Konno, Satoshi Browse this author →KAKEN DB
Keywords: BET bromodomain inhibitor
WEE1 inhibitor
DNA damage repair
nonhomologous end joining
nonsmall cell lung cancer
Issue Date: 15-Feb-2020
Publisher: John Wiley & Sons
Journal Title: International journal of cancer
Volume: 146
Issue: 4
Start Page: 1114
End Page: 1124
Publisher DOI: 10.1002/ijc.32515
PMID: 31199520
Abstract: Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of BET-inhibiting drugs on the expression of oncogenes such as c-Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2-M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775-induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775-induced DNA double-strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET-inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
Rights: This is the peer reviewed version of the following article: International journal of cancer: 146(4): 1114-1124., which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.
Type: article (author version)
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 高島 雄太

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