Combining ATR inhibitors with chloroquine for PDAC

INDICATION: Pancreatic cancer

Cell culture and mouse studies suggest inhibiting ATR and the autophagy inhibitor chloroquine could help treat pancreatic ductal adenocarcinoma (PDAC). Screening of protein kinase inhibitors in a human PDAC cell line pretreated with autophagy inhibitor chloroquine identified four ATR inhibitors -- AZD6738, VX-970 and two tool compounds -- that decreased cell growth compared with no treatment. In a human PDAC cell line co-cultured with human cancer-associated fibroblasts, chloroquine plus one of the tool compounds decreased tumor cell growth compared with either agent alone. In a panel of three other human PDAC cell lines, the combination decreased viability. In xenograft and syngeneic mouse models of PDAC, the combination decreased tumor growth, and in the xenograft model, the combination decreased tumor cell proliferation and apoptosis compared with vehicle. Next steps include testing chloroquine and ATR inhibitors in combination with undisclosed agents...