PD-L1 upregulation accompanied with epithelial-mesenchymal transition attenuates sensitivity to ATR inhibition in p53 mutant pancreatic cancer cells.

Pancreatic cancer is a highly progressive malignant tumor for which there is a critical unmet need for novel therapeutic strategies. A previous study of the authors indicated that VE-821, a selective inhibitor of the ataxia-telangiectasia-mutated and rad3-related protein (ATR), has antitumor efficacy. In this study, the effect of programmed death ligand 1 (PD-L1) on the sensitivity to VE-821 was investigated in p53 mutant pancreatic cancer cells. These results show that BxPC-3 cells exhibited higher sensitivity to VE-821 than mesenchymal PANC-1 cells, which were more migratory and had higher expressions of PD-L1 and CD44. When VE-821 was applied to two cells, epithelial-to-mesenchymal transition (EMT) was induced in PANC-1 cells with concomitant upregulation of PD-L1 and CD44, while BxPC-3 cells did not manifest these changes. Attenuation of PD-L1 expression suppressed VE-821-induced EMT, inhibited cell migration, and downregulated CD44 expression. Furthermore, PD-L1 inhibition partially reversed the activation of AKT/ERK, enhanced DNA damage, and increased VE-821 sensitivity in PANC-1 cells. Analysis of GEPIA data showed positive correlation of PD-L1 expression with EMT-related transcription factors. Taken together, these results suggest a novel function of PD-L1 in regulating response to ATR inhibition. These data highlight PD-L1 inhibition as a promising target to enhance sensitivity to ATR inhibitors in mesenchymal pancreatic cancer.