{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T07:17:14Z","timestamp":1778570234811,"version":"3.51.4"},"posted":{"date-parts":[[2026,5,8]]},"group-title":"Cancer Biology","reference-count":54,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T00:00:00Z","timestamp":1778198400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"name":"NIH\/NCI","award":["CA275990"],"award-info":[{"award-number":["CA275990"]}]},{"name":"NIH\/NCI","award":["CA278889"],"award-info":[{"award-number":["CA278889"]}]},{"DOI":"10.13039\/100000892","name":"Prostate Cancer Foundation","doi-asserted-by":"crossref","award":["FP00016492"],"award-info":[{"award-number":["FP00016492"]}],"id":[{"id":"10.13039\/100000892","id-type":"DOI","asserted-by":"crossref"}]},{"name":"DoD CDMRP","award":["PC230358"],"award-info":[{"award-number":["PC230358"]}]},{"DOI":"10.13039\/100004917","name":"CPRIT","doi-asserted-by":"crossref","award":["RR190021"],"award-info":[{"award-number":["RR190021"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,5,8]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>\n                  Immune checkpoint B7-H3 is an emerging target for immunotherapy. DS-7300a is an advanced B7-H3-targeting antibody-drug conjugate (ADC) warheaded with the topoisomerase I inhibitor DXd. DS-7300a has demonstrated clinical activity, but molecular biomarkers to predict its therapeutic response remain elusive.\n                  <jats:italic>TP53<\/jats:italic>\n                  is one of the most mutated tumor suppressor genes across cancers, and effective therapies are urgently needed for\n                  <jats:italic>TP53<\/jats:italic>\n                  -deficient cancers. Using prostate cancer (PCa) as a model system, we reported that DS-7300a\u2019s anti-tumor efficacy is highly dependent on functional p53 in cancer cells, and\n                  <jats:italic>TP53<\/jats:italic>\n                  defects confer resistance to DS-7300a. Mechanistically, we found that DS-7300a and its payload, DXd, induce DNA damage and activate the ATM\/ATR\/CHK signaling cascade, thereby stabilizing p53 and inducing a pro-apoptotic and senescence-associated transcriptome. In contrast,\n                  <jats:italic>TP53<\/jats:italic>\n                  -deficient cells fail to detect DXd-induced DNA damage, maintain a high proliferation rate, and exhibit low levels of apoptosis and senescence, thereby conferring resistance to DS-7300a. Ferroptosis is an iron-dependent form of regulated cell death triggered by lipid peroxidation, which is mechanistically and morphologically distinct from apoptosis. Interestingly, DS-7300a treatment elevates lipid peroxidation in TP53-deficient cancer cells and upregulates glutathione peroxidase 4 (GPX4), an antioxidant enzyme that mitigates lipid peroxidation. Using isogeneic xenograft models and a newly developed humanized B7-H3 PCa model, we demonstrated that inducing ferroptosis by pharmacological inhibition of GPX4 enhances DS-7300a\u2019s efficacy in\n                  <jats:italic>TP53<\/jats:italic>\n                  -deficient tumors. Our studies demonstrate that TP53 status dictates anti-tumor responses to DS-7300a, and ferroptosis induction represents a promising therapeutic approach to overcome resistance to DS-7300a in malignancies harboring TP53 defects.\n                <\/jats:p>","DOI":"10.64898\/2026.05.05.722958","type":"posted-content","created":{"date-parts":[[2026,5,8]],"date-time":"2026-05-08T22:55:21Z","timestamp":1778280921000},"source":"Crossref","is-referenced-by-count":0,"title":["Improve the Efficacy of B7-H3-Targeting Antibody-Drug Conjugate DS-7300a in TP53-deficient Tumors by Inducing Ferroptosis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1150-7003","authenticated-orcid":false,"given":"Javier","family":"Leo","sequence":"first","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Feiyu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chenling","family":"Meng","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianlin","family":"Gu","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yaman","family":"Albittar","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhen","family":"Fan","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jie","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Boyi","family":"Gan","sequence":"additional","affiliation":[{"name":"Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sangeeta","family":"Goswami","sequence":"additional","affiliation":[{"name":"Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"},{"name":"Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA"},{"name":"James P. 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