%0 Journal Article %T Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation %+ Centre Léon Bérard [Lyon] %+ Institut de Cancérologie de Strasbourg Europe (ICANS) %+ CRLCC Paul Strauss %+ Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC) %+ Institut Pluridisciplinaire Hubert Curien (IPHC) %A Waissi, Waisse %A Nicol, Anaïs %A Jung, Matthieu %A Rousseau, Marc %A Jarnet, Delphine %A Noel, Georges %A Burckel, Hélène %< avec comité de lecture %@ 2072-6694 %J Cancers %I MDPI %V 13 %N 3 %P 527 %8 2021-02 %D 2021 %R 10.3390/cancers13030527 %M 33573176 %K DNA repair %K PARP inhibitor %K gemcitabine %K pancreatic cancer %K proton therapy %K radiotherapy %K transcriptome. %Z Life Sciences [q-bio] %Z Life Sciences [q-bio]/Human health and pathologyJournal articles %X Over the past few years, studies have focused on the development of targeted radiosensitizers such as poly(ADP-ribose) polymerase inhibitors. We performed an in vivo study and a whole-transcriptome analysis to determine whether PARP inhibition enhanced gemcitabine-based chemoradiosensitization of pancreatic cancer xenografts, combined with either proton or photon irradiation. NMRI mice bearing MIA PaCa-2 xenografts were treated with olaparib and/or gemcitabine and irradiated with 10 Gy photon or proton. First, a significant growth inhibition was obtained after 10 Gy proton irradiation compared to 10 Gy photon irradiation (p = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine (p = 0.05), olaparib (p = 0.034) or proton therapy (p < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy (p = 0.024). Simultaneously, whole RNA sequencing profiling showed differentially expressed genes implicated in categories such as DNA repair, type I interferon signaling and cell cycle. Moreover, a large amount of lncRNA was dysregulated after proton therapy, gemcitabine and olaparib. This is the first study showing that addition of olaparib to gemcitabine-based chemoradiotherapy improved significantly local control in vivo, especially after proton therapy. RNA sequencing profiling analysis presented dynamic alteration of transcriptome after chemoradiation and identified a classifier of gemcitabine response. %G English %2 https://hal.science/hal-03160783/document %2 https://hal.science/hal-03160783/file/PDF%20Datastream.pdf %L hal-03160783 %U https://hal.science/hal-03160783 %~ IN2P3 %~ INSERM %~ DRS-IPHC %~ CNRS %~ IGBMC %~ UNIV-STRASBG %~ FNCLCC %~ STRAUSS %~ IPHC %~ SITE-ALSACE