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

Autor: Hajime Kikuchi, Tetsuaki Shoji, Ichiro Kinoshita, Junko Kikuchi, Yuta Takashima, Megumi Furuta, Makie Maeda, Jun Sakakibara-Konishi, Satoshi Konno, Hirotoshi Dosaka-Akita, Motofumi Suzuki, Eiki Kikuchi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Cancer Research
BRD4
DNA End-Joining Repair
Lung Neoplasms
DNA damage
Cell Cycle Proteins
chemical and pharmacologic phenomena
Pyrimidinones
Heterocyclic Compounds
2-Ring
Piperazines
Mice
03 medical and health sciences
0302 clinical medicine
BET bromodomain inhibitor
Carcinoma
Non-Small-Cell Lung
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Animals
Humans
DNA damage repair
DNA Breaks
Double-Stranded
education
Mitotic catastrophe
WEE1 Inhibitor AZD1775
education.field_of_study
Chemistry
Drug Synergism
hemic and immune systems
Azepines
Protein-Tyrosine Kinases
Triazoles
DNA repair protein XRCC4
Xenograft Model Antitumor Assays
Bromodomain
nonhomologous end joining
DNA-Binding Proteins
Pyridazines
Non-homologous end joining
Oncology
Gene Knockdown Techniques
030220 oncology & carcinogenesis
Cancer research
Pyrazoles
Female
WEE1 inhibitor
Myelin transcription factor 1
Transcription Factors
nonsmall cell lung cancer
Zdroj: International journal of cancer. 146(4):1114-1124
ISSN: 0020-7136
Popis: 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.
Databáze: OpenAIRE
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