IFNA pathway drives the more aggressive phenotype of KRASG12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation

Activating mutations of KRAS play critical roles in the initiation and progression of pancreatic ductal adenocarcinoma (PDAC). Accumulating evidence indicates that distinct KRAS alleles associate with different prognoses, but the underlying mechanisms are not known. We established isogenic KRAS mutants ( KRAS G12D, KRAS G12V, and KRAS WT) using a KRAS G12R patient-derived PDAC cell line by CRISPR/Cas9 knock-in. We used these isogenic cell lines, a collection of characterized human PDAC patient-derived cell lines, and murine PDAC models to study the role of these KRAS alleles in vitro and in vivo . We verified that the growth of KRAS G12D cells is more aggressive compared to KRAS G12V isogenic cells in vitro and in vivo using orthotopic mouse models. Signal transducer and activator of transcription (STAT) activation was the most significant difference between KRAS G12D and KRAS G12V isogenic PDACs. Furthermore, activation of interferon-alpha (IFNA)/IFNA receptor (IFNAR)1/STAT3 signaling in the cancer cells mediated the more aggressive phenotype of KRAS G12D PDACs. Conversely, inhibition of IFNAR1 in patient-derived PDAC cells suppressed tumor growth. Finally, IFNAR1 blockade was also effective in murine PDAC models and induced a significant increase in survival when combined with immune checkpoint blockade therapy. We conclude that the IFNA pathway and IFNAR1/STAT3 axis contribute to a more aggressive tumor progression in human KRAS G12D PDACs and that IFNAR1 inhibition is a potential therapeutic target for overcoming resistance to immunotherapy in PDAC. One Sentence Summary IFNA pathway drives the more aggressive phenotype of KRAS G12D-mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation. ### Competing Interest Statement RKJ received Consultant fees from Elpis, Innocoll, SPARC, SynDevRx; owns equity in Accurius, Enlight, SynDevRx; Serves on the Board of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund, Tekla World Healthcare Fund and received a Research Grant from Boehringer Ingelheim. LLM's spouse is an employee of Bayer. DGD received consultant fees from Innocoll and research grants from Bayer, Surface Oncology, Exelixis and BMS. No reagents or support from these companies was used for this study. No potential conflicts of interest were disclosed by other authors.