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Transl. Med."],"published-print":{"date-parts":[[2025,12,24]]},"abstract":"<jats:p>\n                    Targeting cell cycle checkpoints has emerged as a promising strategy in cancer therapy, yet single-agent inhibitors often fail because of compensatory mechanisms. Here, we demonstrate that coinhibition of ATR (RP-3500) and PKMYT1 (RP-6306) induces synthetic lethality in Rb1-deficient breast cancers by disrupting both S-G\n                    <jats:sub>2<\/jats:sub>\n                    and G\n                    <jats:sub>2<\/jats:sub>\n                    -M checkpoints. This leads to replication stress, premature mitotic entry, and accumulation of DNA damage. In vitro, Rb1-deficient breast cancer cells exhibited marked apoptosis and loss of clonogenic survival, whereas Rb1-proficient models remained resistant to combination treatment. Genetic manipulation confirmed this dependency: Rb1 knockdown sensitized resistant models, whereas reexpression conferred protection. In vivo, patient-derived xenograft (PDX) models recapitulated these findings. Rb1-deficient tumors regressed after ATR\/PKMYT1 coinhibition, whereas Rb1-proficient tumors showed only modest responses. Combination therapy was well tolerated without weight loss or measurable toxicity. Biomarker analysis revealed increased \u03b3H2AX and reduced Ki67 staining exclusively in Rb1-deficient PDX models, underscoring the specificity of this response. Mechanistically, Rb1 loss impaired double-strand DNA repair by attenuating homologous recombination and nonhomologous end joining, leading to replication fork collapse, chromosomal instability, and mitotic catastrophe. Proteogenomic analysis identified JNK\/p38 stress response pathway activation as a key driver of apoptosis after ATR\/PKMYT1 inhibition in Rb1-deficient cells. Clinically, a retrospective analysis of stage IV breast cancer datasets revealed that Rb1-low tumors display reduced DNA repair pathway activity in triple-negative and CDK4\/6 inhibitor\u2013resistant luminal breast cancers. These results identify Rb1 loss as a predictive biomarker for ATR\/PKMYT1-targeted therapy, offering a potential precision treatment strategy for advanced breast cancers.\n                  <\/jats:p>","DOI":"10.1126\/scitranslmed.adx6797","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T18:58:10Z","timestamp":1766602690000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":5,"title":["Rb1 deficiency induces synthetic lethality with ATR and PKMYT1 coinhibition in breast cancer cell lines and patient-derived xenografts"],"prefix":"10.1126","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9367-9766","authenticated-orcid":true,"given":"Xiao-Ting","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."},{"name":"Guangdong Provincial Key Laboratory of 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Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9566-8975","authenticated-orcid":true,"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2365-0327","authenticated-orcid":true,"given":"Linjie","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-0802","authenticated-orcid":true,"given":"Jing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department 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