{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T23:07:17Z","timestamp":1794006437143,"version":"4.8.0"},"reference-count":76,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"734","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,2,14]]},"abstract":"<jats:p>\n            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\n            <jats:italic>TP53<\/jats:italic>\n            mutation status in a panel of\n            <jats:italic>IDH1<\/jats:italic>\n            wild-type (WT) glioblastoma (GBM) patient-derived xenografts (PDXs). AZD1390 suppressed radiation-induced ATM signaling, abrogated G\n            <jats:sub>0<\/jats:sub>\n            -G\n            <jats:sub>1<\/jats:sub>\n            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\n            <jats:italic>TP53<\/jats:italic>\n            -mutant tumors but not in\n            <jats:italic>TP53<\/jats:italic>\n            -WT PDXs. In mechanistic studies, increased endogenous DNA damage and constitutive ATM signaling were observed in\n            <jats:italic>TP53<\/jats:italic>\n            -mutant, but not in\n            <jats:italic>TP53<\/jats:italic>\n            -WT, PDXs. In plasmid-based reporter assays, GBM43 (\n            <jats:italic>TP53<\/jats:italic>\n            -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\n            <jats:italic>TP53<\/jats:italic>\n            (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\n            <jats:italic>TP53<\/jats:italic>\n            -mutant human GBM. Together, our results imply that increased basal ATM signaling and enhanced dependence on HR represent a unique susceptibility of\n            <jats:italic>TP53<\/jats:italic>\n            -mutant cells to ATM inhibitor\u2013mediated radiosensitization.\n          <\/jats:p>","DOI":"10.1126\/scitranslmed.adj5962","type":"journal-article","created":{"date-parts":[[2024,2,14]],"date-time":"2024-02-14T19:00:09Z","timestamp":1707937209000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":53,"title":["Aberrant ATM signaling and homology-directed DNA repair as a vulnerability of p53-mutant GBM to AZD1390-mediated radiosensitization"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-8413-5970","authenticated-orcid":true,"given":"Jiajia","family":"Chen","sequence":"first","affiliation":[{"name":"Department of Radiation Oncology, Mayo Clinic, Rochester, MN 55905, USA."},{"name":"Department of Oncology, Shengjing Hospital of China Medical University, Shenyang 110004, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4529-2302","authenticated-orcid":true,"given":"Daniel J.","family":"Laverty","sequence":"additional","affiliation":[{"name":"Department of Environmental Health, Harvard T. 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