Affiliation:
1. Department of General Surgery Shanghai Key Laboratory of Gastric Neoplasms Shanghai Institute of Digestive Surgery Ruijin Hospital Shanghai Jiao Tong University School of Medicine Shanghai 200025 P. R. China
2. Department of Gastric Cancer Surgery Fudan University Shanghai Cancer Center Department of Oncology Shanghai Medical College Fudan University Shanghai 200032 P. R. China
3. Shanghai Center for Bioinformation Technology Shanghai Engineering Research Center of Pharmaceutical Translation & Shanghai Industrial Technology Institute Shanghai 202163 P. R. China
Abstract
AbstractErlotinib, an EGFR tyrosine kinase inhibitor, is used for treating patients with cancer exhibiting EGFR overexpression or mutation. However, the response rate of erlotinib is low among patients with gastric cancer (GC). The findings of this study illustrated that the overexpression of bromodomain PHD finger transcription factor (BPTF) is partially responsible for erlotinib resistance in GC, and the combination of the BPTF inhibitor AU‐1 with erlotinib synergistically inhibited tumor growth both in vivo and in vitro. AU‐1 inhibited the epigenetic function of BPTF and decreased the transcriptional activity of c‐MYC on PLCG1 by attenuating chromosome accessibility of the PLCG1 promoter region, thus decreasing the expression of p‐PLCG1 and p‐Erk and eventually improving the sensitivity of GC cells to erlotinib. In patient‐derived xenograft (PDX) models, AU‐1 monotherapy exhibited remarkable tumor‐inhibiting activity and is synergistic anti‐tumor effects when combined with erlotinib. Altogether, the findings illustrate that BPTF affects the responsiveness of GC to erlotinib by epigenetically regulating the c‐MYC/PLCG1/pErk axis, and the combination of BPTF inhibitors and erlotinib is a viable therapeutic approach for GC.
Funder
National Natural Science Foundation of China
Natural Science Foundation of Shanghai Municipality
Subject
General Physics and Astronomy,General Engineering,Biochemistry, Genetics and Molecular Biology (miscellaneous),General Materials Science,General Chemical Engineering,Medicine (miscellaneous)