Weihao Lin, Chungui Xu, Chaoqun Liu, Rui Zhou
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, characterized by poor survival rates and limited therapeutic options. Oncogenic KRAS mutations are frequent in pancreatic cancer patients and are key drivers of tumorigenesis. Recent studies have underscored the essential role of extracellular signal-regulated kinase (ERK) in sustaining KRAS-mutant tumors and mediating resistance to KRAS-ERK-targeted therapies. However, the specific prognostic value of KRAS-ERK-associated genes in KRAS-mutant pancreatic cancer remains largely undefined. In this study, we performed a comprehensive analysis of molecular stratification based on KRAS-ERK-associated genes and established a five-gene KRAS-ERK prognosis signature (KEPS) comprising ARNTL2, ZWILCH, KIAA0513, KIAA0913, and C4orf43. The KEPS model effectively stratified patients into high- and low-risk groups, with significantly poorer prognosis observed in the high-risk group. External validation using independent KRAS-mutant pancreatic cancer cohorts validated the prognostic performance of KEPS. Further analyses revealed that the high-risk group was enriched in tumor progression-related pathways and exhibited elevated expression of immune checkpoint molecules, including PD-L1, PD-L2, and CD276. Among the KEPS signature genes, ARNTL2 was prioritized for further functional characterization. In two anti-PD-L1-treated cohorts, ARNTL2 correlated with immune checkpoint expression and therapeutic response, suggesting potential relevance to immune checkpoint blockade. Functional assays confirmed that ARNTL2 depletion suppressed malignant phenotypes of KRAS-mutant PDAC cells in vitro and impaired tumor growth in vivo. In conclusion, this work establishes KEPS as a novel molecular tool for risk stratification in KRAS-mutant pancreatic cancer and highlights that ARNTL2 may represent a potential personalized therapeutic target.