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Cisplatin resistance is complex and multifactorial, involving DNA repair via nucleotide excision repair (NER), increased detoxification activities, and overexpression of lysine deacetylases (KDACs), which reduce chromatin accessibility and alter transcriptional regulation. Combining cisplatin with KDAC inhibitors has shown promise, often attributed to increased drug sensitivity through higher chromatin accessibility; however, this hypothesis has not been validated. Here, we synthesized a novel Pt(IV) derivative, ctc-[Pt(NH3)2(VPA)(PhB)Cl2] (cPVP), which combines cisplatin with two KDAC inhibitors, phenylbutyrate and valproic acid. Compared with cisplatin, cPVP induced significantly greater cytotoxicity, and increased DNA damage formation. High-resolution mapping of genomic cisplatin damage and repair indicated that enhanced sensitivity resulted not from altered chromatin accessibility, but from increased drug uptake and the inhibition of NER. Moreover, cPVP prevented the development of resistance to both cisplatin and itself in cancer cells. Together, these results establish the inhibition of nucleotide excision repair, rather than enhanced damage sensitivity due to chromatin accessibility, as the primary mechanism by which KDAC-targeting cisplatin prodrugs overcome resistance to platinum-based therapies.<\/jats:p>","DOI":"10.3390\/biom16040542","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T09:40:31Z","timestamp":1775554831000},"page":"542","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Cisplatin-Based Prodrug Inhibits Nucleotide Excision Repair Independently of Chromatin Accessibility to Overcome Resistance"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3911-1043","authenticated-orcid":false,"given":"Ya\u2019ara","family":"Negev-Korem","sequence":"first","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"},{"name":"The Myers Skin Research Laboratory, Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9103401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3372-9717","authenticated-orcid":false,"given":"Hadar","family":"Golan-Berman","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisheva","family":"Heilbrun","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7142-3359","authenticated-orcid":false,"given":"Marina","family":"Fru\u0161i\u0107-Zlotkin","sequence":"additional","affiliation":[{"name":"The Myers Skin Research Laboratory, Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9103401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-5603-983X","authenticated-orcid":false,"given":"Ofer","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular Genetics, The Institute for Medical Research Israel-Canada, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiba","family":"Hassanain","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular 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Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1631-4018","authenticated-orcid":false,"given":"Dan","family":"Gibson","sequence":"additional","affiliation":[{"name":"Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112102, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7268-9845","authenticated-orcid":false,"given":"Ron","family":"Kohen","sequence":"additional","affiliation":[{"name":"The Myers Skin Research Laboratory, Institute for Drug Research, School of Pharmacy, The Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9103401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9767-3740","authenticated-orcid":false,"given":"Sheera","family":"Adar","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Molecular 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