AGER-dependent macropinocytosis drives resistance to KRAS-G12D–targeted therapy in advanced pancreatic cancer
Menée à l'aide de xénogreffes dérivées de tumeurs de patients et à l'aide de modèles murins d'adénocarcinome canalaire du pancréas, cette étude met en évidence un mécanisme par lequel la macropinocytose dépendante du récepteur AGER favorise la résistance des cellules cancéreuses aux thérapies ciblant les mutations KRAS-G12D
Pancreatic ductal adenocarcinoma (PDAC) driven by the KRAS-G12D mutation presents a formidable health challenge because of limited treatment options. MRTX1133 is a highly selective and first-in-class KRAS-G12D inhibitor under clinical development. Here, we report that the advanced glycosylation end product–specific receptor (AGER) plays a key role in mediating MRTX1133 resistance in PDAC cells. The up-regulation of AGER within cancer cells instigates macropinocytosis, facilitating the internalization of serum albumin and subsequent amino acid generation. These amino acids are then used to synthesize the antioxidant glutathione, leading to resistance to MRTX1133 treatment due to the inhibition of apoptosis. The underlying molecular mechanism involves AGER’s interaction with diaphanous-related formin 1 (DIAPH1), a formin protein responsible for driving Rac family small GTPase 1 (RAC1)–dependent macropinosome formation. The effectiveness and safety of combining MRTX1133 with pharmacological inhibitors of the AGER-DIAPH1 complex (using RAGE299) or macropinocytosis (using EIPA) were confirmed in patient-derived xenografts, orthotopic models, and genetically engineered mouse PDAC models. This combination therapy also induces high-mobility group box 1 (HMGB1) release, resulting in a subsequent antitumor CD8+ T cell response in immunocompetent mice. Collectively, the study findings underscore the potential to enhance the efficacy of KRAS-G12D blockade therapy by targeting AGER-dependent macropinocytosis. AGER-driven macropinocytosis contributes to resistance against KRAS-G12D–targeted therapy in pancreatic ductal adenocarcinoma. Selective KRAS-G12D inhibitors have become an important treatment option for patients with KRAS-G12D–driven cancers, but the development of drug resistance can limit their efficacy. In this study by Li et al., the authors found that advanced glycosylation end product–specific receptor (AGER) contributed to MRTX1133 resistance in pancreatic ductal adenocarcinoma (PDAC) through modulation of macropinocytosis and glutathione synthesis using patient-derived xenografts and orthotopic and genetically engineered mouse models. The combination of MRTX1133 with inhibition of AGER or macropinocytosis improved survival and reduced tumor burden in a CD8+ T cell–dependent manner. These results suggest that this combination treatment may be an effective strategy to improve MRTX1133 efficacy in KRAS-G12D–driven PDAC and related cancers. —Allison Williams
https://www.science.org/doi/abs/10.1126/scitranslmed.adp4986