Format

Send to

Choose Destination
EMBO Mol Med. 2017 Apr;9(4):482-497. doi: 10.15252/emmm.201606975.

Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts.

Author information

1
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.
2
Hôpital Nord, Marseille, France.
3
CIC1409, AP-HM-Hôpital Nord, Aix-Marseille Université, Marseille, France.
4
Institut Paoli-Calmettes, Marseille, France.
5
Hôpital de la Timone, Marseille, France.
6
Programme Cartes d'Identité des Tumeurs (CIT), Ligue Nationale Contre Le Cancer, Paris, France.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
8
Laboratory of Epigenetics and Chromatin Dynamics, Departments of Biochemistry and Molecular Biology and Medicine, Mayo Clinic, Rochester, MN, USA.
9
Centre Interdisciplinaire de Nanoscience de Marseille-CNRS UMR 7325, Parc Scientifique et Technologique de Luminy, Aix-Marseille Université, Marseille, France.
10
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.

Abstract

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 JQ1 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.

KEYWORDS:

c‐MYC ; JQ1; bromodomains; pancreatic adenocarcinoma; transcriptomic signature

PMID:
28275007
PMCID:
PMC5376755
DOI:
10.15252/emmm.201606975
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center