IFNA pathway drives the more aggressive phenotype of KRAS G12D -mutant pancreatic ductal adenocarcinomas via IFNAR1/STAT3 activation
Year: 2022
Type: preprint
Abstract: 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.
Authors: Koetsu Inoue, Daniel H. Schanne, Aya Matsui, Pinji Lei, Sebastian Klein, Shuichi Aoki, Hajime Taniguchi, Hiroto Kikuchi, Jiang Chen, Zelong Liu, Shengdar Q. Tsai, Tyge CE Schmidt, Masaaki Iwasaki, Glenn Geidel, Alexander Koch, Peigen Huang, Dai Fukumura, Toshihiro Shioda, Lance L. Munn, Carlos Fernandez-del Castillo, Theodore S. Hong, Rakesh K. Jain, Andrew Liss, Nabeel Bardeesy, Dan G. Duda
Institutions: Harvard University, Tohoku University, Massachusetts General Hospital, University of Freiburg, University Medical Center Freiburg, Tokyo Women's Medical University, University Hospital Cologne, Keio University, Sir Run Run Shaw Hospital, Zhejiang University, University Medical Center Hamburg-Eppendorf
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: G1423657041, G3631430387, G3865632432, G4119534169, G4931028366, ROLE AND BIOMARKER VALUE FOR PLASMA HGF IN SUSCEPTIBILITY TO HIGH-DOSE RADIATION-INDUCED LIVER DYSFUNCTION, G5555468294, G5850682332, MECHANISMS MEDIATING THE IMMUNE RESPONSE AFTER PROTON VERSUS PHOTON RADIOTHERAPY IN IDH-MUTANT LIVER CANCER, G7930908297, G7954887892, G9000016775, G9000066029, G9000148505, G9000338353, A Phase II and Biomarker Study of Dual VEGF/PD-L1 Blockade in Neoadjuvant Setting in Resectable HCC Patients
OpenAlex ID: W4283754504