Endocrine Abstracts (2017) 50 P242 | DOI: 10.1530/endoabs.50.P242

Combination of JQ1, an inhibitor of epigenetic pathways, and everolimus for treatment of pancreatic and bronchial neuroendocrine tumours

Kate E Lines1, Mark Stevenson1, Panagis Filippakopoulos2, Simona Grozinsky-Glasberg3, Chas Bountra2 & Rajesh V Thakker1

1University of Oxford, Oxford, UK; 2Structural Genomics Consortium, University of Oxford, Oxford, UK; 3Hadassah-Hebrew University Medical Centre, Jerusalem, Israel.

Current treatments, including surgery, medical therapy, radiotherapy, and radionuclide therapy for neuroendocrine tumours of the pancreas (PNETs) and bronchus (BNETs) are often unsatisfactory, leading to a 5-year survival of <50% and 5%, respectively. PNETs and BNETs frequently have mutations in chromatin-remodelling genes and the protein encoded by the multiple endocrine neoplasia type 1 (MEN1) gene, menin. Menin binds the histone methyltransferase MLL1 and together with the acetyl-lysine recognising bromo and extra terminal (BET) family proteins plays an important role in tumour development. We have previously demonstrated that the BET inhibitor JQ1 can significantly decrease proliferation, and increase apoptosis of BNET and PNET cells in vitro, and PNETs in vivo. JQ1 treatment, however, did not lead to 100% cell death, and we therefore investigated for such effects using JQ1 in combination with everolimus, an inhibitor of the mechanistic target of rapamycin (mTOR) pathway. Treatment of the metastatic PNET cell line BON-1, and the less aggressive typical bronchial carcinoid cell line, H727, by everolimus alone reduced proliferation by 30% (P<0.005), and 40% (P<0.05), respectively, whilst JQ1 alone reduced proliferation by 70% and 50% (both P<0.0005), respectively, when compared to control treated cells. Furthermore, JQ1, but not everolimus, significantly increased apoptosis of BON-1 and H727 cells (2.7- and 3.3-fold respectively, P<0,0005). Combined JQ1 and everolimus treatment of BON-1 and H727 cells reduced proliferation by 86% (P<0.0005), and 81% (P<0.0005), respectively, when compared to control treated cells; this was also significantly (P<0.0005) higher than cells treated with JQ1 only. Furthermore, combined JQ1 and everolimus treatment of BON-1 and H727 cells increased apoptosis by 2.6-fold and 4.7-fold (both P<0.0005), respectively, when compared, to cells treated with JQ1 only. In conclusion, our results demonstrate that combined treatment of JQ1 and everolimus may provide a potential therapeutic regime for PNETs and BNETs.

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