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.
Highlights
The global burden of cancer continues to increase largely because of an aging population and an increasing adoption of cancer-causing life style behaviours [1]
Initial screening with a small library of 19 epigenetic probes was performed in three gastric cancer (GC) cell lines, but only 5 compounds (Bromosporine, UN1999, UNC0638, (+)-JQ1 and PNZ5) inhibited the growth of the cells at a concentration of 10 μM after 72h incubation (Supplementary Table 1). (+)-JQ1 and PNZ5 were the most active compounds, with strong antiproliferative activity and were chosen for further investigation (Figure 1B)
The effect on fluorescence recovery was stronger than seen for the single domain mutant N140F of the first bromodomain or N433F of the second bromodomain, respectively. These findings suggested that PNZ5 effectively displaced both bromodomains of ectopically expressed BRD4 from chromatin
Summary
The global burden of cancer continues to increase largely because of an aging population and an increasing adoption of cancer-causing life style behaviours [1]. Gastric cancer is an aggressive disease, and its prognosis remains poor, generally owing to the absence of specific symptoms that renders early diagnosis of this disease difficult [4]. About half of GC patients have recurrent disease after curative surgery, but the outcome for these patients is still very poor, with an estimated 5-year survival rate for locoregional disease of 25% - 35% [5, 6]. A recent ‘Trastuzumab for Gastric Cancer’ (ToGA) trial successfully demonstrated trastuzumab (Trastuzumab®) a recombinant humanized monoclonal antibody that targets the extracellular domain IV of the HER2 protein, as the first biologic therapy to have activity in advanced GC. There is an urgent need to introduce new therapeutic agents for the clinical management of gastric cancer
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