Background: Pancreatic ductal adenocarcinoma (PADA) represents a devastating type of pancreatic cancer with high mortality. Defining a prognostic gene signature that can stratify patients with different risk will benefit cancer treatment strategies.

Methods: Gene expression profiles of PADA patients were acquired from the Cancer Genome Atlas and Gene Expression Omnibus, including GSE62452 and GSE28735. Differential expression analysis was carried out using the package edgeR in R. Intro-tumor immune infiltrates were quantified by six different computational algorithms XCELL, TIMER, QUANTISEQ, MCPCOUNTER, EPIC, and CIBERSORT. Biological processes were investigated based on R package “clusterProfiler”.

Results: 13 genes (ARNTL2, BHLHE40, FBXL17, FBXL8, PPP1CB, RBM4B, ADRB1, CCAR2, CDK1, CSNK1D, KLF10, PSPC1, SIAH2) were eligible for the development of a prognostic gene signature. Performance of the prognostic gene signature was assessed in the discovery set (n = 210), validation set (n = 52), and two external data set (GSE62452, n = 65, and GSE28735, n = 84). Area under the curve (AUC) for predicting 3-year overall survival was 0.727, 0.732, 0.700, and 0.658 in the training set, the validation set, and the two test sets, respectively. KM curve revealed that the low-risk group had an improved prognosis than the high-risk group in all four datasets. PCA analysis demonstrated that the low-risk group was apparently separated from the high-risk group. CD8 T cell and B cell were significantly reduced in the high-risk group than in the low-risk group, while neutrophils were significantly augmented in the high-risk group than in the low-risk group. BMS-536924, Foretinib, Linsitinib, and Sabutoclax were more sensitive in the low-risk group, whereas Erlotinib was more effective in the high-risk group.

Conclusions: We successfully established and verified a novel circadian clock-related gene signature, which could stratify patients with different risk and be reflective of the therapeutic effect of molecular targeted therapy. Our findings could incorporate the pharmacological modulation of circadian clock into future therapeutic strategies.