Impact of STAT3 phosphorylation in glioblastoma stem cells radiosensitization and patient outcome

// Konstantin Masliantsev 1, 2, 3 , Baptiste Pinel 4 , Anaïs Balbous 1, 2, 3 , Pierre-Olivier Guichet 1, 2, 3 , Gaëlle Tachon 1, 2, 3 , Serge Milin 5 , Julie Godet 5 , Mathilde Duchesne 5 , Antoine Berger 4 , Christos Petropoulos 1, 2, 3 , Michel Wager 2, 6 and Lucie Karayan-Tapon 1, 2, 3 1 Inserm U1084, Laboratoire de Neurosciences Expérimentales et Cliniques, Poitiers F-86073, France 2 Université de Poitiers, Poitiers F-86073, France 3 CHU de Poitiers, Laboratoire de Cancérologie Biologique, Poitiers F-86022, France 4 CHU de Poitiers, Service d’Oncologie Radiothérapique, Poitiers F-86021, France 5 CHU de Poitiers, Service d’Anatomo-Cytopathologie, Poitiers F-86021, France 6 CHU de Poitiers, Service de Neurochirurgie, Poitiers F-86021, France Correspondence to: Lucie Karayan-Tapon, email: lucie.karayan-tapon@chu-poitiers.fr Keywords: glioblastoma; Stat3; radioresistance; cancer stem cells; static Received: October 26, 2017      Accepted: November 29, 2017      Published: December 16, 2017 ABSTRACT Glioblastoma (GBM) represents the most common and lethal primary malignant brain tumor. The standard treatment for glioblastoma patients involves surgical resection with concomitant radio and chemotherapy. Despite today’s clinical protocol, the prognosis for patients remains very poor with a median survival of 15 months. Tumor resistance and recurrence is strongly correlated with a subpopulation of highly radioresistant and invasive cells termed Glioblastoma Stem Cells (GSCs). The transcription factor STAT3 has been found to be constitutively activated in different tumors including GBM and enhanced tumor radioresistance. In this study, we assessed radiosensitization of GSC lines isolated from patients by inhibition of STAT3 activation using Stattic or WP1066. We showed that inhibitor treatment before cell irradiation decreased the surviving fraction of GSCs suggesting that STAT3 inhibition could potentiate radiation effects. Finally, we investigated STAT3 activation status on 61 GBM clinical samples and found a preferential phosphorylation of STAT3 on Serine727 (pS727). Moreover, we found that pS727 was associated with a significant lower overall patient survival and progression-free survival but not pY705. Taken together, our results suggest that pS727-STAT3 could be a potential prognostic marker and could constitute a therapeutic target to sensitize highly radioresistant GSCs.