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

Abstract

Simple SummaryPancreatic ductal adenocarcinoma is a devastating disease and an extremely chemoresistant tumour. In the present manuscript, we described the role of BPTF during tumour pancreatic ductal adenocarcinoma progression and in response to gemcitabine treatment, a gold standard treatment in this tumour type. Through different genetic approaches, we reduced BPTF levels in a panel of pancreatic ductal adenocarcinoma cell lines. We validated its therapeutic effect in cell cultures and in mouse models of pancreatic cancer. A reduction in BPTF levels impaired cell proliferation and sensitized pancreatic tumour cells to gemcitabine. We demonstrated that BPTF-silencing reduced the expression of several ABC-transporters, which are involved in gemcitabine resistance, and enhanced its accumulation in the tumour cell, improving its therapeutic effect.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.