Development of resistance to BET bromodomain inhibitor JQ1 and demonstration of epithelial-mesenchymal transition in pancreatic cancer cells.

e15263 Background: Pancreatic ductal adenocarcinoma (PDAC) continues to be the leading cause of cancer related death in part due to limited efficacy of conventional chemotherapy. As such, there is increasing interest in developing inhibitors targeting epigenetic changes, including targeting BET proteins that bind acetylated histones to regulate gene transcription. We have found that the BET-inhibitor JQ1 is effective against pancreatic cancer cells. Since cancer cells can develop resistance to targeted therapies, we examined whether it was possible for PDAC cells to develop resistance to JQ1. Methods: The PDAC cell line CD18 cells (CD18-P) were treated with increasing concentration of JQ1 over a prolonged period of time to develop JQ1-resistent cells (CD18-JQ1r). We also generated CD18 cells resistant to 5-fluorouracil (CD18-CR) by treating CD18-P cells with increasing concentration of 5-fluorouracil. Results: Unlike CD18-P, CD18-JQ1r cells were resistant to the effects of JQ1 in 3D collagen. Moreover, JQ...