EPISHIFT: A NEW PARADIGM IN CHEMOSENSITIVITY MODULATION IN PDAC TROUGH EPIGENETIC.

FRAUNHOFFER NICOLAS A.; ABUELAFIA, ANALIA MEILERMAN; REMY, NICOLLE; GAYET, ODILE; DUSETTI, NELSON; IOVANNA, JUAN

Paris

Encuentro; 52nd Meeting of the European Pancreatic Club,; 2020

European Pancreatic club

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal types ofcancer. One of the major impediments to the treatment of this disease is the highmolecular heterogeneity, which is transduced in variable susceptibility to drugs andsurvival. Recent studies have pointed out that PDAC heterogeneity andchemosensitivity are explained by the transcriptome and consequently for a specificepigenetic program. The aim of this study was to analyze if the epigenetic modulationof PDAC transcriptome is associated with a change in the chemosensitivity response.Materials and methods: To select the study cohort, initially, we characterized thechemosensitivity response to 6 chemotherapeutic drugs (chemodrugs) on 54 PDAC-derived cell lines (PDCLs) using a multiparametric approach. Thereafter, we selected17 PDCLs that characterize the observed range of chemosensitivity. Ten epigeneticdrugs (epidrugs) at a low-cytotoxic concentration were used to modulate both activationand repressive histone marks on the 17 PDCLs. The epidrugs concentrations and theglobal epigenetic modulation were determined by cytotoxic assays and western blot,respectively. RNA-Seq was performed on the 17 PDCLs after 72 hrs of treatment withthe epidrugs. The changes in the chemosensitivity were analyzed in a scheme of pre-treatment with the epidrugs and consequently treatment with the chemodrugs.Results: Transcriptomic analysis revealed two types of response to the epidrugs:general and selective. General response was characterized by the modulation on thesame pathways in all the PDCLs. Contrary, selective response was PDCL dependentwith a specific set of genes affected by each epidrug. Resistant PDCLschemosensitivity was modulated strongly by the general response inhibitors while thesensitive PDCL maintained their chemosensitivity profile. Conclusions: These resultsopen a new paradigm in PDAC chemosensitivity response through the modulation ofthe epigenetic landscape. Moreover, we confirm the association among the phenotypeand the chemodrugs resistance profile.