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However, resistance and treatment\u2010limiting toxicities frequently emerge during repeated administration, underscoring an unmet need for strategies to overcome ADC failure. In this study, we investigated whether inhibition of ataxia telangiectasia and Rad3\u2010related protein (ATR) could enhance the antitumor efficacy of antibody\u2010mimetic drug conjugates (AMDCs), a targeted payload delivery platform. Combination treatment with a duocarmycin\u2010bearing HER2\u2010targeted AMDC (Duo\u2010HER2) and an ATR inhibitor markedly enhanced antitumor activity in a human HER2\u2010positive breast cancer xenograft model. In a limited cohort of treated mice, this combination induced sustained tumor suppression, with prolonged tumor\u2010free survival exceeding 100\u2009days. Although transient body weight loss was observed during the early phase of treatment, no evidence of overt systemic toxicity was detected. Synergistic interactions with Duo\u2010HER2 were further confirmed in\u00a0vitro using three clinically relevant ATR inhibitors\u2014tuvusertib, ceralasertib, and berzosertib. Short\u2010term apoptosis analyses revealed only modest induction of cell death, whereas longer\u2010term viability assays demonstrated pronounced growth suppression. Cell cycle analyses showed S\u2010phase accumulation accompanied by a mild increase in the sub\u2010G1 population, suggesting that the combination initially exerts a cytostatic effect through replication stress\u2013induced S\u2010phase arrest, followed by delayed cytotoxicity. Together, these findings indicate that Duo\u2010HER2 combined with ATR inhibitors synergistically suppresses tumor growth in HER2\u2010positive breast cancer models. Further studies employing optimized formulations, expanded in\u00a0vivo cohorts, and additional tumor models will be required to fully define the therapeutic potential of this strategy and its relevance for overcoming ADC resistance.<\/jats:p>","DOI":"10.1002\/cam4.72071","type":"journal-article","created":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:20:48Z","timestamp":1783398048000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Duocarmycin\u2010Bearing Antibody\u2010Mimetic Drug Conjugate Combined With an\n                    <scp>ATR<\/scp>\n                    Inhibitor Results in Complete Tumor Regression in a\n                    <scp>KPL<\/scp>\n                    \u20104 Xenograft 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