Radiosensitizing Pancreatic Cancer with PARP Inhibitor and Gemcitabine: An In Vivo and a Whole-Transcriptome Analysis after Proton or Photon Irradiation.

Fiche publication

Date publication

janvier 2021

Journal

Cancers

Auteurs

Membres identifiés du Cancéropôle Est :
Pr NOEL Georges , Dr BURCKEL Hélène , Mme NICOL Anaïs

Tous les auteurs :
Waissi W, Nicol A, Jung M, Rousseau M, Jarnet D, Noel G, Burckel H

Lien Pubmed

https://www.ncbi.nlm.nih.gov/pubmed/33573176

Résumé

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 ( = 0.046). Moreover, the combination of olaparib, gemcitabine and proton therapy significantly sensitized tumor xenografts, compared to gemcitabine ( = 0.05), olaparib ( = 0.034) or proton therapy ( < 0.0001) alone or to the association of olaparib, gemcitabine and radiotherapy ( = 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.