title: Chromatin Regulators as a Guide for Cancer Treatment Choice.
abstract: The limited capacity to predict a patient's response to distinct chemotherapeutic agents is a major hurdle in cancer management. The efficiency of a large fraction of current cancer therapeutics (radio- and chemotherapies) is influenced by chromatin structure. Reciprocally, alterations in chromatin organization may affect resistance mechanisms. Here, we explore how the misexpression of chromatin regulators-factors involved in the establishment and maintenance of functional chromatin domains-can inform about the extent of docetaxel response. We exploit Affymetrix and NanoString gene expression data for a set of chromatin regulators generated from breast cancer patient-derived xenograft models and patient samples treated with docetaxel. Random Forest classification reveals specific panels of chromatin regulators, including key components of the SWI/SNF chromatin remodeler, which readily distinguish docetaxel high-responders and poor-responders. Further exploration of SWI/SNF components in the comprehensive NCI-60 dataset reveals that the expression inversely correlates with docetaxel sensitivity. Finally, we show that loss of the SWI/SNF subunit BRG1 (SMARCA4) in a model cell line leads to enhanced docetaxel sensitivity. Altogether, our findings point toward chromatin regulators as biomarkers for drug response as well as therapeutic targets to sensitize patients toward docetaxel and combat drug resistance. Mol Cancer Ther; 15(7); 1768-77. ©2016 AACR.
authors.affiliation: Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellisée Ligue contre le Cancer, Paris, France. Sorbonne Universités, UPMC Universite Paris 06, CNRS, UMR3664, Paris, France. zachary.gurard-levin@curie.fr genevieve.almouzni@curie.fr.
authors.forename: Zachary A
authors.initials: ZA
authors.lastname: Gurard-Levin
authors.affiliation: Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellisée Ligue contre le Cancer, Paris, France. Sorbonne Universités, UPMC Universite Paris 06, CNRS, UMR3664, Paris, France.
authors.forename: Laurence O W
authors.initials: LO
authors.lastname: Wilson
authors.affiliation: Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez, Almagro, Madrid, Spain.
authors.forename: Vera
authors.initials: V
authors.lastname: Pancaldi
authors.affiliation: DITEP (Département d'Innovations Thérapeutiques et Essais Précoces), Gustave Roussy, France. Inserm Unit U981, Gustave Roussy, Villejuif, France. Université Paris Saclay, Université Paris-Sud, Faculté de Médicine, Le Kremlin Bicêtre, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Postel-Vinay
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Fabricio G
authors.initials: FG
authors.lastname: Sousa
authors.affiliation: Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France.
authors.forename: Cecile
authors.initials: C
authors.lastname: Reyes
authors.affiliation: Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Marangoni
authors.affiliation: Institut Curie, PSL Research University, Translational Research Department, Genomics Platform, Paris, France.
authors.forename: David
authors.initials: D
authors.lastname: Gentien
authors.affiliation: Spanish National Cancer Research Centre (CNIO), c/Melchor Fernandez, Almagro, Madrid, Spain.
authors.forename: Alfonso
authors.initials: A
authors.lastname: Valencia
authors.affiliation: Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Yves
authors.initials: Y
authors.lastname: Pommier
authors.affiliation: Institut Curie, Medical Oncology, Paris, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Cottu
authors.affiliation: Institut Curie, PSL Research University, CNRS, UMR3664, Equipe Labellisée Ligue contre le Cancer, Paris, France. Sorbonne Universités, UPMC Universite Paris 06, CNRS, UMR3664, Paris, France. zachary.gurard-levin@curie.fr genevieve.almouzni@curie.fr.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Almouzni
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor; D002843:Chromatin / Q000235:genetics* / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000187:drug effects*; D016000:Cluster Analysis; D019295:Computational Biology / Q000379:methods; D030541:Databases, Genetic; D000077143:Docetaxel; D020869:Gene Expression Profiling; D020043:Genes, Essential; D006801:Humans; D008954:Models, Biological; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D000071185:Pharmacogenomic Testing; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D043823:Taxoids / Q000494:pharmacology; D050257:Tubulin Modulators / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D002843:Chromatin; D043823:Taxoids; D050257:Tubulin Modulators; D000077143:Docetaxel