AGER, also known as the receptor for advanced glycation end-products (RAGE), is a cell surface transmembrane multiligand receptor. It is encoded by the AGER gene and is mainly expressed in the lung. AGER involves multiple pathways such as NFκB, Akt, p38, and MAP kinases, initiating and perpetuating a pro-inflammatory state. It has significance in various biological processes related to inflammation, apoptosis, and immunity [2].

In pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation, up-regulation of AGER in cancer cells leads to macropinocytosis. This process facilitates the internalization of serum albumin, generation of amino acids, synthesis of antioxidant glutathione, and ultimately resistance to MRTX1133 treatment by inhibiting apoptosis. The mechanism involves AGER's interaction with DIAPH1 to drive RAC1-dependent macropinosome formation. Combining MRTX1133 with inhibitors of the AGER-DIAPH1 complex or macropinocytosis was effective and safe in patient-derived xenografts, orthotopic models, and genetically engineered mouse PDAC models, and also induced an antitumor CD8+ T cell response [1]. In sepsis, AGER-mediated lipid peroxidation drives caspase-11 inflammasome activation in macrophages. Inhibition of this pathway via ALOX5 limits caspase-11 inflammasome activation and pyroptosis. Pharmacologic inhibition or depletion of AGER in myeloid cells protects against lipopolysaccharide-induced septic death in poly(I:C)-primed mice [3].

In summary, AGER plays a crucial role in inflammation-related processes and disease development. In PDAC, it mediates resistance to targeted therapy, and in sepsis, it drives inflammasome activation. Studies using mouse models, including genetically engineered mouse PDAC models and poly(I:C)-primed mice with AGER depletion, have been instrumental in uncovering these functions, providing potential therapeutic targets for these diseases.

References:

1. Li, Changfeng, Liu, Yuanda, Liu, Chang, Tang, Daolin, Kang, Rui. 2025. AGER-dependent macropinocytosis drives resistance to KRAS-G12D-targeted therapy in advanced pancreatic cancer. In Science translational medicine, 17, eadp4986. doi:10.1126/scitranslmed.adp4986. https://pubmed.ncbi.nlm.nih.gov/39879317/

2. Serveaux-Dancer, Marine, Jabaudon, Matthieu, Creveaux, Isabelle, Blanchon, Loïc, Sapin, Vincent. 2019. Pathological Implications of Receptor for Advanced Glycation End-Product (AGER) Gene Polymorphism. In Disease markers, 2019, 2067353. doi:10.1155/2019/2067353. https://pubmed.ncbi.nlm.nih.gov/30863465/

3. Chen, Ruochan, Zhu, Shan, Zeng, Ling, Tang, Daolin, Kang, Rui. 2019. AGER-Mediated Lipid Peroxidation Drives Caspase-11 Inflammasome Activation in Sepsis. In Frontiers in immunology, 10, 1904. doi:10.3389/fimmu.2019.01904. https://pubmed.ncbi.nlm.nih.gov/31440260/