Faculty Collaboration Database

Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts. EMBO Mol Med 2017 Apr;9(4):482-497

Date

03/10/2017

Pubmed ID

28275007

Pubmed Central ID

PMC5376755

DOI

10.15252/emmm.201606975

Scopus ID

2-s2.0-85014779112 (requires institutional sign-in at Scopus site)   58 Citations

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.

Author List

Bian B, Bigonnet M, Gayet O, Loncle C, Maignan A, Gilabert M, Moutardier V, Garcia S, Turrini O, Delpero JR, Giovannini M, Grandval P, Gasmi M, Ouaissi M, Secq V, Poizat F, Nicolle R, Blum Y, Marisa L, Rubis M, Raoul JL, Bradner JE, Qi J, Lomberk G, Urrutia R, Saul A, Dusetti N, Iovanna J

Authors

Gwen Lomberk PhD Professor in the Surgery department at Medical College of Wisconsin
Raul A. Urrutia MD Center Director, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adult
Aged
Aged, 80 and over
Animals
Antineoplastic Agents
Azepines
Cell Survival
Cells, Cultured
Female
Gene Expression Profiling
Heterografts
Humans
Male
Mice
Middle Aged
Pancreatic Neoplasms
Precision Medicine
Triazoles