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

Benjamin Bian, Martin Bigonnet, Odile Gayet, Celine Loncle, Aurélie Maignan, Marine Gilabert, Vincent Moutardier, Stephane Garcia, Olivier Turrini, Jean Robert Delpero, Marc Giovannini, Philippe Grandval, Mohamed Gasmi, Mehdi Ouaissi, Veronique Secq, Flora Poizat, Rémy Nicolle, Yuna Blum, Laetitia Marisa, Marion RubisJean Luc Raoul, James E. Bradner, Jun Qi, Gwen Lomberk, Raul Urrutia, Andres Saul, Nelson Dusetti, Juan Iovanna

Research output: Contribution to journalArticle

21 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)482-497
Number of pages16
JournalEMBO Molecular Medicine
Volume9
Issue number4
DOIs
StatePublished - Apr 1 2017

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Precision Medicine
Gene Expression Profiling
Pancreatic Neoplasms
Heterografts
Neoplasms
Primary Cell Culture
Cell Cycle Checkpoints
Transcriptome
Transcription Factors
Cell Proliferation
Apoptosis
Staining and Labeling
Survival
Therapeutics
Genes

Keywords

  • bromodomains
  • c-MYC
  • JQ1
  • pancreatic adenocarcinoma
  • transcriptomic signature

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1 : implications for individualized medicine efforts. / Bian, Benjamin; Bigonnet, Martin; Gayet, Odile; Loncle, Celine; Maignan, Aurélie; Gilabert, Marine; Moutardier, Vincent; Garcia, Stephane; Turrini, Olivier; Delpero, Jean Robert; Giovannini, Marc; Grandval, Philippe; Gasmi, Mohamed; Ouaissi, Mehdi; Secq, Veronique; Poizat, Flora; Nicolle, Rémy; Blum, Yuna; Marisa, Laetitia; Rubis, Marion; Raoul, Jean Luc; Bradner, James E.; Qi, Jun; Lomberk, Gwen; Urrutia, Raul; Saul, Andres; Dusetti, Nelson; Iovanna, Juan.

In: EMBO Molecular Medicine, Vol. 9, No. 4, 01.04.2017, p. 482-497.

Research output: Contribution to journalArticle

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 2017, 'Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts', EMBO Molecular Medicine, vol. 9, no. 4, pp. 482-497. https://doi.org/10.15252/emmm.201606975
Bian, Benjamin ; Bigonnet, Martin ; Gayet, Odile ; Loncle, Celine ; Maignan, Aurélie ; Gilabert, Marine ; Moutardier, Vincent ; Garcia, Stephane ; Turrini, Olivier ; Delpero, Jean Robert ; Giovannini, Marc ; Grandval, Philippe ; Gasmi, Mohamed ; Ouaissi, Mehdi ; Secq, Veronique ; Poizat, Flora ; Nicolle, Rémy ; Blum, Yuna ; Marisa, Laetitia ; Rubis, Marion ; Raoul, Jean Luc ; Bradner, James E. ; Qi, Jun ; Lomberk, Gwen ; Urrutia, Raul ; Saul, Andres ; Dusetti, Nelson ; Iovanna, Juan. / Gene expression profiling of patient-derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1 : implications for individualized medicine efforts. In: EMBO Molecular Medicine. 2017 ; Vol. 9, No. 4. pp. 482-497.
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AU - Bian, Benjamin

AU - Bigonnet, Martin

AU - Gayet, Odile

AU - Loncle, Celine

AU - Maignan, Aurélie

AU - Gilabert, Marine

AU - Moutardier, Vincent

AU - Garcia, Stephane

AU - Turrini, Olivier

AU - Delpero, Jean Robert

AU - Giovannini, Marc

AU - Grandval, Philippe

AU - Gasmi, Mohamed

AU - Ouaissi, Mehdi

AU - Secq, Veronique

AU - Poizat, Flora

AU - Nicolle, Rémy

AU - Blum, Yuna

AU - Marisa, Laetitia

AU - Rubis, Marion

AU - Raoul, Jean Luc

AU - Bradner, James E.

AU - Qi, Jun

AU - Lomberk, Gwen

AU - Urrutia, Raul

AU - Saul, Andres

AU - Dusetti, Nelson

AU - Iovanna, Juan

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