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

in Science translational medicine by 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 Harley, William F Elmquist, Zachary D Nagel, Shiv K Gupta, Jann N Sarkaria

TLDR

  • This study tested a drug called AZD1390 that can make cancer cells more sensitive to radiation therapy. The researchers found that the drug works better on cancer cells that have a mutation in a gene called p53. The study also showed that the drug works by blocking a protein called ATM, which helps cells repair damage from radiation. The researchers hope that this drug could be used to treat brain tumors in the future.

Abstract

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 ofmutation status in a panel ofwild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G-Garrest, 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.

Overview

  • The study evaluates 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 is a brain-penetrant ATM inhibitor and a potent radiosensitizer. The study tested the radiosensitizing effects of AZD1390 in WT and p53-mutant GBM in vitro and in vivo.

Comparative Analysis & Findings

  • AZD1390 suppressed radiation-induced ATM signaling, abrogated G-Garrest, 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 p53-mutant tumors but not in WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in p53-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 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 p53-mutant human GBM. Together, the results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of p53-mutant cells to ATM inhibitor-mediated radiosensitization.

Implications and Future Directions

  • The study highlights the importance of p53 mutation status in determining the radiosensitizing effects of AZD1390. The findings suggest that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of p53-mutant cells to ATM inhibitor-mediated radiosensitization. Future research should focus on identifying other genetic or epigenetic markers that may predict response to ATM inhibitors in GBM and other cancers. Additionally, further mechanistic studies are needed to understand the underlying molecular mechanisms of ATM inhibitor-mediated radiosensitization in p53-mutant cells.
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