Open AccessGene expression profiling of patient‐derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ 1: implications for individualized medicine efforts
Author(s) -
Bian Benjamin,
Bigonnet Martin,
Gayet Odile,
Loncle Celine,
Maignan Aurélie,
Gilabert Marine,
Moutardier Vincent,
Garcia Stephane,
Turrini Olivier,
Delpero JeanRobert,
Giovannini Marc,
Grandval Philippe,
Gasmi Mohamed,
Ouaissi Mehdi,
Secq Veronique,
Poizat Flora,
Nicolle Rémy,
Blum Yuna,
Marisa Laetitia,
Rubis Marion,
Raoul JeanLuc,
Bradner James E,
Qi Jun,
Lomberk Gwen,
Urrutia Raul,
Saul Andres,
Dusetti Nelson,
Iovanna Juan
Publication year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201606975
Subject(s) - bromodomain , cancer research , pancreatic cancer , gene expression profiling , bet inhibitor , medicine , gene expression , cancer , gene , biology , microbiology and biotechnology , epigenetics , genetics
c‐ MYC controls 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 JQ 1 treatment compared to MYC ‐low cells, in monolayer, 3D cultured spheroids and in vivo xenografted 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.