雷达51
突变体
DNA修复
DNA损伤
生物
DNA
同源重组
细胞生物学
放射增敏剂
癌症研究
信号转导
遗传学
基因
医学
放射治疗
内科学
作者
Jiajia Chen,Daniel J. Laverty,Surabhi Talele,Ashwin Bale,Brett L. Carlson,Kendra A. Porath,Katrina K. Bakken,Danielle M. Burgenske,Paul A. Decker,Rachael A. Vaubel,Jeanette E. Eckel‐Passow,Rohit Bhargava,Zhenkun Lou,Petra Hamerlik,Brendan A.C. Harley,William F. Elmquist,Zachary D. Nagel,Shiv K. Gupta,Jann N. Sarkaria
标识
DOI:10.1126/scitranslmed.adj5962
摘要
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 TP53 mutation status in a panel of IDH1 wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G 0 -G 1 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 TP53 -mutant tumors but not in TP53 -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in TP53 -mutant, but not in TP53 -WT, PDXs. In plasmid-based reporter assays, GBM43 ( TP53 -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 TP53 (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 TP53 -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of TP53 -mutant cells to ATM inhibitor–mediated radiosensitization.
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