BET inhibition as a new strategy for the treatment of gastric cancer

// Raquel C. Montenegro 1, 2, 4 , Peter G.K. Clark 3 , Alison Howarth 2 , Xiao Wan 6 , Alessandro Ceroni 2 , Paulina Siejka 1, 2 , Graciela A. Nunez-Alonso 1, 2 , Octovia Monteiro 1, 2 , Catherine Rogers 1, 2 , Vicki Gamble 1, 2 , Rommel Burbano 4 , Paul E. Brennan 1, 2 , Cynthia Tallant 1, 2 , Daniel Ebner 2 , Oleg Fedorov 1, 2 , Eric O’Neill 6 , Stefan Knapp 1, 2, 5 , Darren Dixon 3 , Susanne Muller 1, 2 1 The Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7DQ, UK 2 Target Discovery Institute, Nuffield Department of Medicine, University of Oxford, Headington, Oxford OX3 7FZ, UK 3 Department of Chemistry, Chemistry Research Laboratory, University of Oxford, Oxford OX1 3TA, UK 4 Federal University of Para, Institute of Biological Sciences, Belem, Para 66075-110, Brazil 5 Institute for Pharmaceutical Chemistry and Buchmann Institute for Life Sciences, Frankfurt am Main D-60438, Germany 6 CRUK/MRC Oxford Institute of Radiation Biology, University of Oxford, Headington OX3 7DQ, UK Correspondence to: Raquel C. Montenegro, email: rcm.montenegro@gmail.com Susanne Muller, email: susanne.muller-knapp@sgc.ox.ac.uk Keywords: epigenetic, bromodomain, BET inhibitors, cytotoxicity, gastric cancer Received: December 11, 2015      Accepted: May 04, 2016      Published: June 01, 2016 ABSTRACT 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.