Activating PIK3CA mutations,present in up to 40%of hormone receptor-positive(HR^(+)),human epidermal growth factor receptor 2-negative(Her2^(-))breast cancer(BC)patients,can be effectively targeted with the alpha isof...Activating PIK3CA mutations,present in up to 40%of hormone receptor-positive(HR^(+)),human epidermal growth factor receptor 2-negative(Her2^(-))breast cancer(BC)patients,can be effectively targeted with the alpha isoform-specific Pl3K inhibitor Alpelisib.This treatment significantly improves outcomes for HR^(+),Her2^(-),and PIK3CA-mutated metastatic BC patients.However,acquired resistance,often due to aberrant activation of the mTOR complex 1(mTORC1)pathway,remains a significant clinical challenge.Our study,using in vitro and orthotopic xenograft mouse models,demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism.Mechanistically,mTORC1 suppresses the induction of autophagy during metabolic perturbation,leading to energy stress,a critical depletion of aspartate,and ultimately cell death.Supporting this mechanism,BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metaboliclly active drugs InBC patients,high mTORC1 activity,indicated by 4E-BP1^(T37/46) phosphorylation correlated with p62 accumulation,a sign of impaired autophagy.Together,these markers predicted poor overall survival in multiple BC subgroups.Our findings reveal that aberrant mTORC1 signaling,a common cause of PI3K inhibitor resistance in BC,creates a druggable metabolic vulnerability by suppressing autophagy.Additionall,the combination of 4E-BP1^(T37/46) phosphorylation and p62 accumulation serves as a biomarker for poor overall survival,suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.展开更多
基金support provided by the Core Facilities for Metabolomics,Flow Cytometry,Cellular Imaging,Preclinical Imagingthe animal facility at Philipps-University of Marburg.N.G.was supported by the Clinician Scientist program(SUCCESS-program)of the Philipps-University of Marburg,the University Cancer Center(UCT)Frankfurt-Marburg+6 种基金the University Hospital of Giessen and Marburg(UKGM)research grants of the Deutsche Forschungsgemeinschaft(GRK 2573/2-2024)University Medical Center Giessen and Marburg(UKGM)(3/2022 MR to N.G.)von Behring-Rontgen-Stiftung(70_0027 to N.G.)Stiftung P.E.Kempkes(01/2021 to N.G.)Medizinstiftung(04/2021 to N.G.)M.F.F.reports funding from the Deutsche Forschungsgemeinschaft(INST 90/1048-1 FUGG).
文摘Activating PIK3CA mutations,present in up to 40%of hormone receptor-positive(HR^(+)),human epidermal growth factor receptor 2-negative(Her2^(-))breast cancer(BC)patients,can be effectively targeted with the alpha isoform-specific Pl3K inhibitor Alpelisib.This treatment significantly improves outcomes for HR^(+),Her2^(-),and PIK3CA-mutated metastatic BC patients.However,acquired resistance,often due to aberrant activation of the mTOR complex 1(mTORC1)pathway,remains a significant clinical challenge.Our study,using in vitro and orthotopic xenograft mouse models,demonstrates that constitutively active mTORC1 signaling renders PI3K inhibitor-resistant BC exquisitely sensitive to various drugs targeting cancer metabolism.Mechanistically,mTORC1 suppresses the induction of autophagy during metabolic perturbation,leading to energy stress,a critical depletion of aspartate,and ultimately cell death.Supporting this mechanism,BC cells with CRISPR/Cas9-engineered knockouts of canonical autophagy genes showed similar vulnerability to metaboliclly active drugs InBC patients,high mTORC1 activity,indicated by 4E-BP1^(T37/46) phosphorylation correlated with p62 accumulation,a sign of impaired autophagy.Together,these markers predicted poor overall survival in multiple BC subgroups.Our findings reveal that aberrant mTORC1 signaling,a common cause of PI3K inhibitor resistance in BC,creates a druggable metabolic vulnerability by suppressing autophagy.Additionall,the combination of 4E-BP1^(T37/46) phosphorylation and p62 accumulation serves as a biomarker for poor overall survival,suggesting their potential utility in identifying BC patients who may benefit from metabolic therapies.
