Targeting BPTF Sensitizes Pancreatic Ductal Adenocarcinoma to Chemotherapy by Repressing ABC-Transporters and Impairing Multidrug Resistance (MDR)

Abstract

Pancreatic ductal adenocarcinoma (PDA) is characterized by an extremely poor prognosis due to its late diagnosis and strong chemoresistance to the current treatments. Therefore, finding new therapeutic targets is an urgent need nowadays. In this study, we report the role of the chromatin remodeler BPTF (Bromodomain PHD Finger Transcription Factor) as a therapeutic target in PDA. BPTF-silencing dramatically reduced cell proliferation and migration in vitro and in vivo in human and mouse PDA cell lines. Moreover, BPTF-silencing reduces the IC50 of gemcitabine in vitro and enhanced its therapeutic effect in vivo. Mechanistically, BPTF is required for c-MYC recruitment to the promoter of ABC-transporters and its downregulation facilitates gemcitabine accumulation in tumour cells, increases DNA damage, and a generates a strong synergistic effect in vivo. We show that BPTF is a therapeutic target in pancreatic ductal adenocarcinoma due to its strong effect on proliferation and in response to gemcitabine.

Keywords

• BPTF
• pancreatic cancer
• ABC-transporters
• multidrug resistance
• gemcitabine