title: Metabolic Response to Everolimus in Patient-Derived Triple-Negative Breast Cancer Xenografts.
abstract: Patients with triple-negative breast cancer (TNBC) are unresponsive to endocrine and anti-HER2 pharmacotherapy, limiting their therapeutic options to chemotherapy. TNBC is frequently associated with abnormalities in the PI3K/AKT/mTOR signaling pathway; drugs targeting this pathway are currently being evaluated in these patients. However, the response is variable, partly due to heterogeneity within TNBC, conferring a need to identify biomarkers predicting response and resistance to targeted therapy. In this study, we used a metabolomics approach to assess response to the mTOR inhibitor everolimus in a panel of TNBC patient-derived xenografts (PDX) (n = 103 animals). Tumor metabolic profiles were acquired using high-resolution magic angle spinning magnetic resonance spectroscopy. Partial least-squares-discriminant analysis on relative metabolite concentrations discriminated treated xenografts from untreated controls with an accuracy of 67% (p = 0.003). Multilevel linear mixed-effects models (LMM) indicated reduced glycolytic lactate production and glutaminolysis after treatment, consistent with PI3K/AKT/mTOR pathway inhibition. Although inherent metabolic heterogeneity between different PDX models seemed to hinder prediction of treatment response, the metabolic effects following treatment were more pronounced in responding xenografts compared to nonresponders. Additionally, the metabolic information predicted p53 mutation status, which may provide complementary insight into the interplay between PI3K signaling and other drivers of disease progression.
authors.affiliation: Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.
authors.forename: Leslie R
authors.identifier: 0000-0002-7199-7042
authors.initials: LR
authors.lastname: Euceda
authors.affiliation: Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.|Department of Radiology, St. Olavs University Hospital , Trondheim 7030, Norway.
authors.forename: Deborah K
authors.initials: DK
authors.lastname: Hill
authors.affiliation: Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.
authors.forename: Endre
authors.initials: E
authors.lastname: Stokke
authors.affiliation: Genetics Department, Institut Curie, PSL Research University , Paris CEDEX 05, France.|Faculty of Pharmacy, Aleppo University , Aleppo 3355, Syria.
authors.forename: Rana
authors.initials: R
authors.lastname: Hatem
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University , Paris CEDEX 05, France.
authors.forename: Rania
authors.initials: R
authors.lastname: El Botty
authors.affiliation: Genetics Department, Institut Curie, PSL Research University , Paris CEDEX 05, France.|EA7331, University of Paris Descartes , Paris CEDEX 06, France.
authors.forename: Ivan
authors.initials: I
authors.lastname: Bièche
authors.affiliation: Translational Research Department, Institut Curie, PSL Research University , Paris CEDEX 05, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.|Department of Radiology, St. Olavs University Hospital , Trondheim 7030, Norway.
authors.forename: Tone F
authors.initials: TF
authors.lastname: Bathen
authors.affiliation: Department of Circulation and Medical Imaging, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.|Department of Laboratory Medicine, Children's and Women's Health, NTNU, The Norwegian University of Science and Technology , Trondheim 7489, Norway.
authors.forename: Siver A
authors.initials: SA
authors.lastname: Moestue
mesh_terms: D000818:Animals; D000068338:Everolimus / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D064593:Heterografts / Q000187:drug effects; D006801:Humans; D055442:Metabolome / Q000187:drug effects*; D055432:Metabolomics / Q000379:methods; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000068338:Everolimus; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C546843:mTOR protein, mouse
keywords: HR MAS MRS; PI3K pathway; everolimus; mTOR; metabolomics; triple-negative breast cancer