ATRX loss in glioma results in dysregulation of cell-cycle phase transition and ATM inhibitor radio-sensitization
Tingting Qin, Brendan Mullan, Ramya Ravindran, Dana Messinger, Ruby Siada, Jessica Cummings, Micah Harris, Ashwath Muruganand, Kalyani Pyaram, Zachary Miklja, Mary Reiber, Taylor Garcia, Dustin Tran, Carla Danussi, Jacqueline A. Brosnan‐Cashman, Drew Pratt, Xinyi Zhao, Alnawaz Rehemtulla, Maureen A. Sartor, Sriram Venneti, Alan K. Meeker, Jason T. Huse, Meredith A. Morgan, Pedro R. Löwenstein, María G. Castro, Viveka Nand Yadav, Carl Koschmann
Abstract
ATRX, a chromatin remodeler protein, is recurrently mutated in H3F3A-mutant pediatric glioblastoma (GBM) and isocitrate dehydrogenase (IDH)-mutant grade 2/3 adult glioma. Previous work has shown that ATRX-deficient GBM cells show enhanced sensitivity to irradiation, but the etiology remains unclear. We find that ATRX binds the regulatory elements of cell-cycle phase transition genes in GBM cells, and there is a marked reduction in Checkpoint Kinase 1 (CHEK1) expression with ATRX loss, leading to the early release of G2/M entry after irradiation. ATRX-deficient cells exhibit enhanced activation of master cell-cycle regulator ATM with irradiation. Addition of the ATM inhibitor AZD0156 doubles median survival in mice intracranially implanted with ATRX-deficient GBM cells, which is not seen in ATRX-wild-type controls. This study demonstrates that ATRX-deficient high-grade gliomas (HGGs) display Chk1-mediated dysregulation of cell-cycle phase transitions, which opens a window for therapies targeting this phenotype.