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The base excision repair (BER) pathway, crucial for fixing DNA abasic sites, is driven by apurinic\/apyrimidinic endonuclease 1 (APE1). While APE1 redox function in PDAC has been extensively studied, its endonuclease activity in PDAC homeostasis and therapeutic response remains poorly understood. We created stable, homozygous APE1 endonuclease-reduced PDAC cell lines to examine the effects of impaired BER activity on pancreatic cancer growth and response to treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>CRISPR\/Cas9-mediated editing was used to introduce an E96A mutation into the Pa03C PDAC cell line, generating three clonal mutant cell lines: E96A B1, E96A B4, E96A G8. APE1 expression and activity were verified in vitro through biochemical assays. Cellular responses to genotoxic stress were examined using cytotoxicity, colony formation, and DNA damage assays. Transcriptomic changes were evaluated via RNA sequencing. In vivo tumor growth and metastatic dissemination were studied in orthotopic PDAC mouse models, with and without treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The E96A mutant cell lines exhibited significantly decreased endonuclease activity but showed no changes in redox signaling or APE1 protein expression. Short-term cytotoxic assays revealed no enhancement in acute sensitivity; however, long-term assessment demonstrated a proliferative defect and a vulnerability to genotoxic stress. Quantitation of nuclear and mitochondrial DNA damage showed mutant cells accumulated significantly more damage to both genomes compared to controls. Transcriptomic analysis revealed that the mutant cell lines maintain a stressed phenotype at baseline, which becomes more pronounced following DNA damage. In vivo, E96A mutants had notably lower tumor burden and metastasis without treatment, and the mutation potentiated the effect of the alkylating drug temozolomide, which inhibited tumor growth and metastasis in a dose-dependent manner.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We established the first stable human PDAC cell models deficient in APE1 endonuclease activity. Our findings demonstrate that selective impairment of APE1\u2019s DNA repair function expands therapeutic options by lowering the threshold for effective processing of DNA damage, validating combination treatments with targeted inhibitors and DNA-damaging agents. Targeting APE1 endonuclease activity represents a promising therapeutic strategy for PDAC, capable of suppressing metastatic spread and enhancing tumor responsiveness to genotoxic therapies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13046-026-03705-7","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T11:24:57Z","timestamp":1775129097000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Targeting APE1 endonuclease activity impairs metastasis and enhances genotoxic therapy response in pancreatic cancer"],"prefix":"10.1186","volume":"45","author":[{"given":"Eyram K.","family":"Kpenu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahmut","family":"Mijit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silpa","family":"Gampala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall S.","family":"Wireman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacqueline","family":"Peil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana K.","family":"Mitchell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanya","family":"Haiaty","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rajesh","family":"Sardar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksha","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Millie M.","family":"Georgiadis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa L.","family":"Fishel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark R.","family":"Kelley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"issue":"2","key":"3705_CR1","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1053\/j.gastro.2022.03.056","volume":"163","author":"LD Wood","year":"2022","unstructured":"Wood LD, Canto MI, Jaffee EM, Simeone DM. 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