6533b838fe1ef96bd12a3e3e
RESEARCH PRODUCT
MTOR inhibitor-based combination therapies for pancreatic cancer
Shirley K. KnauerRoland H. StauberWilko WeichertRoland M SchmidChristian VeltkampBenedikt FeuereckerMaximilian ReichertMaximilian ReichertGünter SchneiderGünter SchneiderDieter SaurDieter SaurZonera HassanMatthias WirthOliver H. KrämerChristian SchneeweisRoland RadRoland RadGüralp O. CeyhanZahra DantesAlexander Arltsubject
therapeutic resistance0301 basic medicineCancer ResearchCell SurvivalMAP Kinase Signaling Systempancreatic cancerAntineoplastic AgentsContext (language use)Mechanistic Target of Rapamycin Complex 2mTORC1Mechanistic Target of Rapamycin Complex 1BiologymTORC2BortezomibMice03 medical and health sciencesCell Line TumorPancreatic cancermedicineAnimalsHumansExtracellular Signal-Regulated MAP KinasesMechanistic target of rapamycinPI3K/AKT/mTOR pathwayBenzoxazolesKinaseMTORTOR Serine-Threonine Kinasesmedicine.diseaseddc:3. Good healthPancreatic NeoplasmsPyrimidines030104 developmental biologyOncologybiology.proteinCancer researchCamptothecinTOR Serine-Threonine KinasesPhosphatidylinositol 3-KinaseTranslational TherapeuticsProto-Oncogene Proteins c-aktBiologieCarcinoma Pancreatic Ductaldescription
Background: Although the mechanistic target of rapamycin (MTOR) kinase, included in the mTORC1 and mTORC2 signalling hubs, has been demonstrated to be active in a significant fraction of patients with pancreatic ductal adenocarcinoma (PDAC), the value of the kinase as a therapeutic target needs further clarification. Methods: We used Mtor floxed mice to analyse the function of the kinase in context of the pancreas at the genetic level. Using a dual-recombinase system, which is based on the flippase-FRT (Flp-FRT) and Cre-loxP recombination technologies, we generated a novel cellular model, allowing the genetic analysis of MTOR functions in tumour maintenance. Cross-species validation and pharmacological intervention studies were used to recapitulate genetic data in human models, including primary human 3D PDAC cultures. Results: Genetic deletion of the Mtor gene in the pancreas results in exocrine and endocrine insufficiency. In established murine PDAC cells, MTOR is linked to metabolic pathways and maintains the glucose uptake and growth. Importantly, blocking MTOR genetically as well as pharmacologically results in adaptive rewiring of oncogenic signalling with activation of canonical extracellular signal-regulated kinase and phosphoinositide 3-kinase-AKT pathways. We provide evidence that interfering with such adaptive signalling in murine and human PDAC models is important in a subgroup. Conclusions: Our data suggest developing dual MTORC1/TORC2 inhibitor-based therapies for subtype-specific intervention.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2018-01-02 |