Background:Intrahepatic cholangiocarcinoma(ICC)is a challenging can-cer with an increasing incidence.The Phase III TOPAZ-1/KEYNOTE-966study demonstrated chemo-immunotherapy(CIT)as a significant advance-ment,potentiall...Background:Intrahepatic cholangiocarcinoma(ICC)is a challenging can-cer with an increasing incidence.The Phase III TOPAZ-1/KEYNOTE-966study demonstrated chemo-immunotherapy(CIT)as a significant advance-ment,potentially replacing traditional chemotherapy for advanced biliary tractcancer.Ferroptosis is a crucial process that affects cancer cell survival andtherapy resistance.Although AKT hyperactivation is prevalent in numerouscancers,including ICC,its role in ferroptosis resistance remains unclear.Thisstudy explored whether targeting ferroptosis can enhance CIT response rates,specifically in ICC patients with AKT hyperactivation.Methods:In vivo metabolic CRISPR screening in a KrasG12D/Tp53−/−ICCmouse model was used to identify primary regulators of ferroptosis duringCIT(gemcitabine,cisplatin,and anti-mouse programmed cell death 1 ligand 1).Phosphoenolpyruvate carboxykinase 1(PCK1)was assessed for its role in fer-roptosis and treatment resistance in preclinical models under AKT activationlevels.Molecular and biochemical techniques were used to explore PCK1-relatedresistance mechanisms in AKT-hyperactivated ICC.Results:Under AKT hyperactivation condition,phosphorylated PCK1(pPCK1)promoted metabolic reprogramming,enhancing ubiquinol and menaquinone-4synthesisthrough the mevalonate(MVA)pathway.This cascade was mediated bythe pPCK1-pLDHA-SPRINGlac axis.Inhibiting PCK1 phosphorylation or usingsimvastatin significantly augmented CIT efficacy in preclinical models.Clini-cal data further indicated that phosphorylated AKT(pAKT)-pPCK1 levels mightserve as a biomarker to predict CIT response in ICC.Conclusion:Thisstudy identified the pAKT-pPCK1-pLDHA-SPRINGlac axis asa novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC byassociating glycolytic activation with MVA flux reprogramming.Targeting thisaxis,potentially through statin-based therapies,may offer a strategy to sensitizeICC cells to ferroptosis and improve treatment outcomes.展开更多
基金National Natural Science Foundation of China,Grant/Award Numbers:81874149,82171834,82303832,82403618China Postdoctoral Science Foundation,Grant/Award Number:2024M761039+5 种基金China National Postdoctoral Program for Innovative Talents,Grant/Award Number:BX20240129Postdoctor Project of Hubei Province,Grant/Award Number:2024HBBHCXA035Knowledge Innovation Program of Wuhan-ShuguangProject,Grant/Award Number:2022020801020456Key Research and Development Program of Social Development of Jiangsu Province,Grant/Award Number:BE2022725Suzhou Science and Technology Development Plan Project,Grant/Award Number:SKY2023049Jiangsu Province Seventh 333 High Level(Second Level)Talents Project。
文摘Background:Intrahepatic cholangiocarcinoma(ICC)is a challenging can-cer with an increasing incidence.The Phase III TOPAZ-1/KEYNOTE-966study demonstrated chemo-immunotherapy(CIT)as a significant advance-ment,potentially replacing traditional chemotherapy for advanced biliary tractcancer.Ferroptosis is a crucial process that affects cancer cell survival andtherapy resistance.Although AKT hyperactivation is prevalent in numerouscancers,including ICC,its role in ferroptosis resistance remains unclear.Thisstudy explored whether targeting ferroptosis can enhance CIT response rates,specifically in ICC patients with AKT hyperactivation.Methods:In vivo metabolic CRISPR screening in a KrasG12D/Tp53−/−ICCmouse model was used to identify primary regulators of ferroptosis duringCIT(gemcitabine,cisplatin,and anti-mouse programmed cell death 1 ligand 1).Phosphoenolpyruvate carboxykinase 1(PCK1)was assessed for its role in fer-roptosis and treatment resistance in preclinical models under AKT activationlevels.Molecular and biochemical techniques were used to explore PCK1-relatedresistance mechanisms in AKT-hyperactivated ICC.Results:Under AKT hyperactivation condition,phosphorylated PCK1(pPCK1)promoted metabolic reprogramming,enhancing ubiquinol and menaquinone-4synthesisthrough the mevalonate(MVA)pathway.This cascade was mediated bythe pPCK1-pLDHA-SPRINGlac axis.Inhibiting PCK1 phosphorylation or usingsimvastatin significantly augmented CIT efficacy in preclinical models.Clini-cal data further indicated that phosphorylated AKT(pAKT)-pPCK1 levels mightserve as a biomarker to predict CIT response in ICC.Conclusion:Thisstudy identified the pAKT-pPCK1-pLDHA-SPRINGlac axis asa novel mechanism driving ferroptosis resistance in AKT-hyperactivated ICC byassociating glycolytic activation with MVA flux reprogramming.Targeting thisaxis,potentially through statin-based therapies,may offer a strategy to sensitizeICC cells to ferroptosis and improve treatment outcomes.
