Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization

• Published in: Science translational medicine Vol. 16; no. 734; p. eadj5962
• Main Authors: Chen, Jiajia, Laverty, Daniel J, Talele, Surabhi, Bale, Ashwin, Carlson, Brett L, Porath, Kendra A, Bakken, Katrina K, Burgenske, Danielle M, Decker, Paul A, Vaubel, Rachael A, Eckel-Passow, Jeanette E, Bhargava, Rohit, Lou, Zhenkun, Hamerlik, Petra, Harley, Brendan, Elmquist, William F, Nagel, Zachary D, Gupta, Shiv K, Sarkaria, Jann N
• Format: Journal Article
• Language: English
• Published: United States 14.02.2024
• Subjects: Ataxia Telangiectasia Mutated Proteins - metabolism; DNA Repair - genetics; Glioblastoma - drug therapy; Glioblastoma - genetics; Glioblastoma - radiotherapy; Humans; Pyridines; Quinolones; Signal Transduction; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.adj5962

ATM is a key mediator of radiation response, and pharmacological inhibition of ATM is a rational strategy to radiosensitize tumors. AZD1390 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. This study evaluated the spectrum of radiosensitizing effects and the impact of mutation status in a panel of wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G -G arrest, and promoted a proapoptotic response specifically in p53-mutant GBM in vitro. In a preclinical trial using 10 orthotopic GBM models, AZD1390/RT afforded benefit in a cohort of -mutant tumors but not in -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in -mutant, but not in -WT, PDXs. In plasmid-based reporter assays, GBM43 ( -mutant) showed elevated DNA repair capacity compared with that in GBM14 (p53-WT), whereas treatment with AZD1390 specifically suppressed homologous recombination (HR) efficiency, in part, by stalling RAD51 unloading. Furthermore, overexpression of a dominant-negative (p53DD) construct resulted in enhanced basal ATM signaling, HR activity, and AZD1390-mediated radiosensitization in GBM14. Analyzing RNA-seq data from TCGA showed up-regulation of HR pathway genes in -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of -mutant cells to ATM inhibitor-mediated radiosensitization.