Oncogenic KRAS mutations drive metabolic reprogramming in pancreatic ductal adenocarcinoma(PDAC).Src-homology 2 domaincontaining phosphatase 2(SHP2)is essential for full KRAS activity,and promising dual SHP2/mitogen-a...Oncogenic KRAS mutations drive metabolic reprogramming in pancreatic ductal adenocarcinoma(PDAC).Src-homology 2 domaincontaining phosphatase 2(SHP2)is essential for full KRAS activity,and promising dual SHP2/mitogen-activated protein kinase(MAPK)inhibition is currently being tested in clinical trials.Exploitable metabolic adaptations may contribute to invariably evolving resistance.To understand the metabolic changes induced by dual inhibition,we comprehensively tested human and murine PDAC cell lines,endogenous tumor models,and patient-derived organoids,which are representative of the full spectrum of PDAC molecular subtypes.We found that dual SHP2/mitogen-activated protein kinase kinase(MEK1/2)inhibition induces major alterations in mitochondrial mass and function,impacts reactive oxygen species(ROS)homeostasis and triggers lipid peroxidase dependency.Anabolic pathways,autophagy and glycolysis were also profoundly altered.However,most strikingly,mitochondrial remodeling was evident,persisting into a therapy-resistant state.The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase(GPX4)inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS.The triple combination of SHP2/MEK1/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo.Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.展开更多
基金This study was funded by the German Cancer Aid,Deutsche Krebshilfe,Project ID 70113697(to D.A.R.)the German Research Foundation,Deutsche Forschungsgemeinschaft(DFG),CRC1479(Project ID 441891347,P17 to D.A.R.,P01 to R.Z.,P06 to O.G.,S01 to M.B.and O.S.,S02 to W.R.)+10 种基金supported by the DFG,within CRC1160(Project ID 256073931,Z02),CRC/TRR167(Project ID 259373024,Z01),CRC1453(Project ID 431984000,S01),TRR 359(Project ID 491676693,Z01),and FOR 5476 UcarE(Project ID 493802833,P07)funding from the German Federal Ministry of Education and Research(BMBF)within the Medical Informatics Funding SchemePM4Onco-FKZ 01ZZ2322A.G.A.is supported by the BMBF via EkoEstMed-FKZ 01ZZ2015.O.Gr.is supported by the DFG,within CRC1160(Project ID 256073931,C02),CRC/TRR167(Project ID 259373024,A08),CRC1425(Project ID 422681845,P10),GRK2606(Project ID 423813989)the European Research Council(ERC)through Starting Grant 337689,Proof-of-Concept Grant 966687the EU-H2020-MSCA-COFUND EURIdoc program(No.101034170)L.H.and O.Gr.are supported by the DFG under Germany’s Excellence Strategy(CIBSS-EXC-2189-Project ID 390939984)the Core Facility AMIRCF(DFGRIsources N°RI_00052)for support in MR imagingthe Lighthouse Core Facility of the Medical Faculty,University of Freiburg(Project Numbers 2023/A2-Fol,2021/B3-Fol)the DKTK,and the DFG(Project Number 450392965)The Proteomic Platform-Core Facility was supported by the Medical Faculty of the University of Freiburg to O.S.(2021/A3-Sch2023/A3-Sch).
文摘Oncogenic KRAS mutations drive metabolic reprogramming in pancreatic ductal adenocarcinoma(PDAC).Src-homology 2 domaincontaining phosphatase 2(SHP2)is essential for full KRAS activity,and promising dual SHP2/mitogen-activated protein kinase(MAPK)inhibition is currently being tested in clinical trials.Exploitable metabolic adaptations may contribute to invariably evolving resistance.To understand the metabolic changes induced by dual inhibition,we comprehensively tested human and murine PDAC cell lines,endogenous tumor models,and patient-derived organoids,which are representative of the full spectrum of PDAC molecular subtypes.We found that dual SHP2/mitogen-activated protein kinase kinase(MEK1/2)inhibition induces major alterations in mitochondrial mass and function,impacts reactive oxygen species(ROS)homeostasis and triggers lipid peroxidase dependency.Anabolic pathways,autophagy and glycolysis were also profoundly altered.However,most strikingly,mitochondrial remodeling was evident,persisting into a therapy-resistant state.The resulting vulnerability to the induction of ferroptotic cell death via the combination of vertical SHP2/MEK1/2 with glutathione peroxidase(GPX4)inhibition was largely independent of the PDAC molecular subtype and was confirmed with direct targeting of RAS.The triple combination of SHP2/MEK1/2 inhibition and the ferroptosis-inducing natural compound withaferin A suppressed tumor progression in an endogenous PDAC tumor model in vivo.Our study offers a metabolic leverage point to reinforce RAS pathway interference for targeted PDAC treatment.
