title: Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts.
abstract: c-MYCcontrols more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient-derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC-high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC-low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC-high group and six transcripts increased in the MYC-low group. We validated the ability of these markers panel to identify MYC-high patient-derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC-high patients are more sensitive to JQ1 treatment compared to MYC-low cells, in monolayer, 3D cultured spheroids andin vivoxenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics.
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Benjamin
authors.identifier: 0000-0001-8691-5292
authors.initials: B
authors.lastname: Bian
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Martin
authors.initials: M
authors.lastname: Bigonnet
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Gayet
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Celine
authors.initials: C
authors.lastname: Loncle
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Maignan
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Gilabert
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.|Hôpital Nord, Marseille, France.|CIC1409, AP-HM-Hôpital Nord, Aix-Marseille Université, Marseille, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Moutardier
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.|Hôpital Nord, Marseille, France.
authors.forename: Stephane
authors.initials: S
authors.lastname: Garcia
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.|Institut Paoli-Calmettes, Marseille, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Turrini
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Jean-Robert
authors.initials: JR
authors.lastname: Delpero
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Giovannini
authors.affiliation: Hôpital de la Timone, Marseille, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Grandval
authors.affiliation: Hôpital Nord, Marseille, France.|CIC1409, AP-HM-Hôpital Nord, Aix-Marseille Université, Marseille, France.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Gasmi
authors.affiliation: Hôpital de la Timone, Marseille, France.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Ouaissi
authors.affiliation: Hôpital Nord, Marseille, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Secq
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Flora
authors.initials: F
authors.lastname: Poizat
authors.affiliation: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: Rémy
authors.initials: R
authors.lastname: Nicolle
authors.affiliation: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: Yuna
authors.initials: Y
authors.lastname: Blum
authors.affiliation: Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Marisa
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France.
authors.forename: Marion
authors.initials: M
authors.lastname: Rubis
authors.affiliation: Institut Paoli-Calmettes, Marseille, France.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Raoul
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: Bradner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Qi
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology and Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Gwen
authors.initials: G
authors.lastname: Lomberk
authors.affiliation: Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology and Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Raul
authors.initials: R
authors.lastname: Urrutia
authors.affiliation: Centre Interdisciplinaire de Nanoscience de Marseille-CNRS UMR 7325, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France.
authors.forename: Andres
authors.initials: A
authors.lastname: Saul
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France nelson.dusetti@inserm.fr juan.iovanna@inserm.fr.
authors.forename: Nelson
authors.identifier: 0000-0002-6161-8483
authors.initials: N
authors.lastname: Dusetti
authors.affiliation: Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université and Institut Paoli-Calmettes, Marseille, France nelson.dusetti@inserm.fr juan.iovanna@inserm.fr.
authors.forename: Juan
authors.identifier: 0000-0003-1822-2237
authors.initials: J
authors.lastname: Iovanna
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism*; D001381:Azepines / Q000378:metabolism*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D020869:Gene Expression Profiling; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D010190:Pancreatic Neoplasms / Q000473:pathology*; D057285:Precision Medicine / Q000379:methods; D014230:Triazoles / Q000378:metabolism*
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; D014230:Triazoles
keywords: 
  c‐MYC
  ; JQ1; bromodomains; pancreatic adenocarcinoma; transcriptomic signature