title: Targeting mTOR pathway inhibits tumor growth in different molecular subtypes of triple-negative breast cancers.
abstract: Triple-negative breast cancers (TNBC) are characterized by frequent alterations in the PI3K/AKT/mTOR signaling pathway. In this study, we analyzed PI3K pathway activation in 67 patient-derived xenografts (PDX) of breast cancer and investigated the anti-tumor activity of the mTOR inhibitor everolimus in 15 TNBC PDX with different expression and mutational status of PI3K pathway markers. Expression of the tumor suppressors PTEN and INPP4B was lost in 55% and 76% of TNBC PDX, respectively, while mutations in PIK3CA and AKT1 genes were rare. In 7 PDX treatment with everolimus resulted in a tumor growth inhibition higher than 50%, while 8 models were classified as low responder or resistant. Basal-like, LAR (Luminal AR), mesenchymal and HER2-enriched tumors were present in both responder and resistant groups, suggesting that tumor response to everolimus is not restricted to a specific TNBC subtype. Analysis of treated tumors showed a correlation between tumor response and post-treatment phosphorylation of AKT, increased in responder PDX, while PI3K pathway markers at baseline were not sufficient to predict everolimus response. In conclusion, targeting mTOR decreased tumor growth in 7 out of 15 TNBC PDX tested. Response to everolimus occurred in different TNBC subtypes and was associated with post-treatment increase of P-AKT.
authors.affiliation: Genetics Department, Institut Curie, PSL Research University, Paris, France.|Faculty of Pharmacy, Aleppo University, Aleppo, Syria.
authors.forename: Rana
authors.initials: R
authors.lastname: Hatem
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Rania
authors.initials: R
authors.lastname: El Botty
authors.affiliation: BioPôle Alfort, National Veterinary School of Alfort, Maisons Alfort, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Chateau-Joubert
authors.affiliation: BioPôle Alfort, National Veterinary School of Alfort, Maisons Alfort, France.|INRA, PHASE Department, Paris, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Servely
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Dalila
authors.initials: D
authors.lastname: Labiod
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: de Plater
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Assayag
authors.affiliation: Genetics Department, Institut Curie, PSL Research University, Paris, France.|Translational Research Department, Institut Curie, PSL Research University, Paris, France.|Medical Oncology Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Coussy
authors.affiliation: Genetics Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Callens
authors.affiliation: Genetics Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Vacher
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.|Surgery Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Fabien
authors.initials: F
authors.lastname: Reyal
authors.affiliation: AstraZeneca R&D Cambr idge, CRUK Cambridge Institute, Cambridge, UK.
authors.forename: Sabina
authors.initials: S
authors.lastname: Cosulich
authors.affiliation: Medical Oncology Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Diéras
authors.affiliation: Genetics Department, Institut Curie, PSL Research University, Paris, France.|EA7331, University of Paris Descartes, Paris, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000068338:Everolimus / Q000494:pharmacology*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068338:Everolimus; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: PDX; PI3K pathway; TNBC; mTOR