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We investigated whether inhibition of ataxia telangiectasia and Rad3-related (ATR) kinase by VE-822 (berzosertib) enhances radiation response and whether p53 status is associated with the magnitude of response. HCT116 (p53 wild type), HT29 (p53 mutant), and HCT116 cells with siRNA-mediated p53 knockdown (HCT116 KD) were treated with VE-822 with or without ionizing radiation (RT). Short-term cell viability and long-term clonogenic survival were evaluated. DNA-damage signaling and ATR-pathway activity were assessed by analysis of \u03b3H2AX and phosphorylated CHK1, whereas flow cytometry was used to examine cell-cycle distribution, mitotic entry, and apoptosis. VE-822 IC50 values were 80.8 nM for HCT116, 33.6 nM for HT29, and 19.6 nM for HCT116 KD cells. A low concentration of VE-822 (20 nM, administered 1\u00a0h before RT) had minimal effects in HCT116 cells but reduced viability and clonogenic survival in HCT116 KD cells, particularly when combined with RT. VE-822 reduced pCHK1 and was associated with sustained \u03b3H2AX signaling, with more pronounced effects in HCT116 KD cells. At 24\u00a0h after RT, HCT116 cells predominantly accumulated in G1 with modest apoptosis, whereas HCT116 KD cells showed greater G2\/M accumulation and apoptosis after VE-822 plus RT. Increased phospho-Histone H3 positivity after combined treatment was consistent with increased mitotic entry. These in vitro findings suggest that impaired p53 function is associated with increased sensitivity to combined ATR inhibition and irradiation and support further evaluation of p53 status as a candidate response biomarker.<\/jats:p>","DOI":"10.1007\/s12672-026-05692-9","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:25:03Z","timestamp":1785403503000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["ATR inhibition enhances radiosensitivity in p53-deficient colorectal cancer cells"],"prefix":"10.1007","volume":"17","author":[{"given":"Na","family":"Shen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Zong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuemei","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,30]]},"reference":[{"key":"5692_CR1","doi-asserted-by":"publisher","first-page":"107327482110334","DOI":"10.1177\/10732748211033497","volume":"28","author":"S Xu","year":"2021","unstructured":"Xu S, Sak A, Erol YB. 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The study was conducted in accordance with relevant institutional guidelines and applicable regulations.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1271"}}