{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T17:01:53Z","timestamp":1786122113105,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"NIH","doi-asserted-by":"publisher","award":["T32CA009531"],"award-info":[{"award-number":["T32CA009531"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NIH","doi-asserted-by":"publisher","award":["R00GM149942"],"award-info":[{"award-number":["R00GM149942"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NIH","doi-asserted-by":"publisher","award":["R01CA229535"],"award-info":[{"award-number":["R01CA229535"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"NIH Cancer Center Support","doi-asserted-by":"publisher","award":["P30CA022453"],"award-info":[{"award-number":["P30CA022453"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: With the advent of genome sequencing and its widespread use in the clinic, there is a great need to identify mutational biomarkers that predict therapeutic responses. DNA polymerase beta (Pol\u03b2) and the base excision repair (BER) pathway have been previously implicated as modulators of response to platinum-based chemotherapies and are mutated in as many as 30% of cancers. Methods: Here, we show in a triple-negative breast cancer (TNBC) model that two classes of mutations in Pol\u03b2, reduced catalytic activity (E295K and D256A mutations) and reduced fidelity (I260M), are sufficient to drive cisplatin and carboplatin-specific sensitivity. Cellular response to oxaliplatin in these Pol\u03b2 mutant models is minimal relative to cisplatin and carboplatin. Results: We show that sensitivity is associated with reduced repair of both platinum-induced DNA intrastrand adducts and interstrand crosslinks (ICLs). Downregulation of the upstream BER factor uracil DNA glycosylase (UNG) reverses drug sensitivity, which is consistent with these Pol\u03b2 mutations negatively impacting ICL DNA repair to drive drug sensitivity. In addition, the intrastrand adduct repair readout indicates that these lesions also play a role in the sensitivity observed in Pol\u03b2 mutant models. In vivo studies demonstrate a significant effect on tumor growth delay with cisplatin treatment in tumor xenografts harboring Pol\u03b2 mutations. Conclusions: These results support the potential for using Pol\u03b2 mutations as predictive biomarkers for cisplatin and carboplatin therapies in the clinical setting.<\/jats:p>","DOI":"10.3390\/cancers18162531","type":"journal-article","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T08:01:36Z","timestamp":1786089696000},"page":"2531","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["DNA Polymerase Beta Catalytic and Fidelity Mutations Drive Platinum-Specific Drug Sensitivity"],"prefix":"10.3390","volume":"18","author":[{"given":"Jacob","family":"Lindquist","sequence":"first","affiliation":[{"name":"Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0847-0501","authenticated-orcid":false,"given":"Josh","family":"Heyza","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Institute of Environmental Health Sciences, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1005-1146","authenticated-orcid":false,"given":"Istri","family":"Ndoja","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nasrin","family":"Movahhedin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Yunker","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Cardo-Vila","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, University of Arizona, Tuscon, AZ 85724, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1120-073X","authenticated-orcid":false,"given":"Seongho","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joann","family":"Sweasy","sequence":"additional","affiliation":[{"name":"Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3325-6750","authenticated-orcid":false,"given":"Steve M.","family":"Patrick","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University and Karmanos Cancer Institute, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1930","DOI":"10.1126\/science.7516581","article-title":"Crystal structure of rat DNA polymerase beta: Evidence for a common polymerase mechanism","volume":"264","author":"Sawaya","year":"1994","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3642","DOI":"10.1074\/jbc.274.6.3642","article-title":"The fidelity of DNA polymerase beta during distributive and processive DNA synthesis","volume":"274","author":"Osheroff","year":"1999","journal-title":"J. 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