Gene Expression Profiling of Patient-Derived Pancreatic Cancer Xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: Implications to individualized medicine efforts

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 targets transcripts which expression is increased in the MYC-high group and 6 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 cells 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 both monolayer and 3D cultured spheroids, 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.

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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