{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T03:05:17Z","timestamp":1791255917459,"version":"4.1.0"},"reference-count":125,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T00:00:00Z","timestamp":1768176000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Nucleoside analogs remain central to the treatment of hematologic malignancies and solid tumors, yet resistance frequently occurs, contributing to relapse and disease-related mortality. Rather than arising from a single mechanism, effective nucleoside analog activity requires successful navigation of multiple biological barriers, including cellular uptake, intracellular activation, nucleotide pool balance, genome surveillance, and mitochondrial stress responses. This review integrates recent advances describing how alterations at each of these levels contribute to resistance to nucleoside analog therapies. We further highlight emerging therapeutic strategies centered on small-molecule inhibitors that exploit these vulnerabilities to enhance the efficacy of nucleoside analogs. Together, this integrative perspective supports the need for development of small molecule inhibitors and design of combination approaches aimed at restoring apoptotic competence and improving the use of nucleoside analog-based therapies for the treatment of cancer.<\/jats:p>","DOI":"10.3390\/cells15020130","type":"journal-article","created":{"date-parts":[[2026,1,12]],"date-time":"2026-01-12T07:30:34Z","timestamp":1768203034000},"page":"130","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Enhancing the Nucleoside Analog Response with Translational Therapeutic Approaches to Overcome Resistance"],"prefix":"10.3390","volume":"15","author":[{"given":"Jenna","family":"Thibodeau","sequence":"first","affiliation":[{"name":"Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kian","family":"Hershberger","sequence":"additional","affiliation":[{"name":"Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"MD\/PhD Program, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4087-1269","authenticated-orcid":false,"given":"Sai Samanvitha M.","family":"Ramakrishna","sequence":"additional","affiliation":[{"name":"Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yongwei","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lauren","family":"Timmer","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryce","family":"Brophy","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9638-7358","authenticated-orcid":false,"given":"Katherine","family":"Zhang","sequence":"additional","affiliation":[{"name":"Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Holly","family":"Edwards","sequence":"additional","affiliation":[{"name":"Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2228-3235","authenticated-orcid":false,"given":"Jeffrey W.","family":"Taub","sequence":"additional","affiliation":[{"name":"Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Division of Pediatric Hematology\/Oncology, Children\u2019s Hospital of Michigan, Detroit, MI 48201, USA"},{"name":"Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8748-716X","authenticated-orcid":false,"given":"Yubin","family":"Ge","sequence":"additional","affiliation":[{"name":"Cancer Biology Graduate Program, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA"},{"name":"Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1200\/JCO.2000.18.1.122","article-title":"Phase III Trial of Gemcitabine Plus Cisplatin Versus Cisplatin Alone in Patients With Locally Advanced or Metastatic Non\u2013Small-Cell Lung Cancer","volume":"18","author":"Sandler","year":"2000","journal-title":"J. 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