BET inhibition as a new strategy for the treatment of gastric cancer.
Gastric cancer is one of the most common malignancies and a leading cause of cancer death worldwide. The prognosis of stomach cancer is generally poor as this cancer is not very sensitive to commonly used chemotherapies. Epigenetic modifications play a key role in gastric cancer and contribute to the development and progression of this malignancy. In order to explore new treatment options in this target area we have screened a library of epigenetic inhibitors against gastric cancer cell lines and identified inhibitors for the BET family of bromodomains as potent inhibitors of gastric cancer cell proliferations. Here we show that both the pan-BET inhibitor (+)-JQ1 as well as a newly developed specific isoxazole inhibitor, PNZ5, showed potent inhibition of gastric cancer cell growth. Intriguingly, we found differences in the antiproliferative response between gastric cancer cells tested derived from Brazilian patients as compared to those from Asian patients, the latter being largely resistant to BET inhibition. As BET inhibitors are entering clinical trials these findings provide the first starting point for future therapies targeting gastric cancer.
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.|Federal University of Pará, Institute of Biological Sciences, Belém, Pará 66075-110, Brazil.
Raquel C
RC
Montenegro
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Peter G K
PG
Clark
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Alison
A
Howarth
CRUK/MRC Oxford Institute of Radiation Biology, University of Oxford, Headington OX3 7DQ, UK.
Xiao
X
Wan
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Alessandro
A
Ceroni
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Paulina
P
Siejka
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Graciela A
GA
Nunez-Alonso
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Octovia
O
Monteiro
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Catherine
C
Rogers
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Vicki
V
Gamble
Federal University of Pará, Institute of Biological Sciences, Belém, Pará 66075-110, Brazil.
Rommel
R
Burbano
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Paul E
PE
Brennan
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Cynthia
C
Tallant
Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Daniel
D
Ebner
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Oleg
O
Fedorov
CRUK/MRC Oxford Institute of Radiation Biology, University of Oxford, Headington OX3 7DQ, UK.
Eric
E
O'Neill
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.|Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Frankfurt am Main D-60438, Germany.
Stefan
S
Knapp
Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK.
Darren
D
Dixon
The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK.|Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK.
Susanne
S
Müller
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D044466:Asian People; D001381:Azepines / Q000737:chemistry / Q000494:pharmacology*; D001938:Brazil; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D020869:Gene Expression Profiling; D057809:HEK293 Cells; D006801:Humans; D007555:Isoxazoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism; D013274:Stomach Neoplasms / Q000208:ethnology / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*; D000092468:Bromodomain Containing Proteins
D001381:Azepines; D018797:Cell Cycle Proteins; D007555:Isoxazoles; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human
BET inhibitors; bromodomain; cytotoxicity; epigenetic; gastric cancer