{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T18:22:25Z","timestamp":1774549345683,"version":"3.50.1"},"reference-count":57,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T00:00:00Z","timestamp":1774483200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100013030","name":"William and Ella Owens Medical Research Foundation","doi-asserted-by":"publisher","award":["10418050"],"award-info":[{"award-number":["10418050"]}],"id":[{"id":"10.13039\/100013030","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Pancreatic ductal adenocarcinoma (PDAC) is highly treatment resistant and characterized by a hypoxic microenvironment. Here, we investigated the role of hypoxia-inducible factor 1\u03b1 (HIF1\u03b1) in regulating resistance to radiation and KRAS-inhibitor. We employed CRISPR\/Cas9 to knock out (KO) HIF1\u03b1 from the murine KRAS\n                    <jats:sup>G12D\/+<\/jats:sup>\n                    ; p53\n                    <jats:sup>R172H\/+<\/jats:sup>\n                    KPC and the KRAS\n                    <jats:sup>G12D\/+<\/jats:sup>\n                    ; p53\n                    <jats:sup>R273H<\/jats:sup>\n                    ; CDK2NA\n                    <jats:sup>-\/-<\/jats:sup>\n                    Panc-1 human pancreatic cell lines. Compared to WT, the HIF1\u03b1 KO cell lines demonstrated a shift toward an epithelial phenotype and had decreased proliferation and migration under hypoxia. HIF1\u03b1 KO cell lines were less likely to survive after radiotherapy, and neutral comet assays demonstrated DNA damage four hours after treatment, suggesting that HIF1\u03b1 promotes radioresistance through non-homologous end joining. When treated with a KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    inhibitor, HIF1\u03b1 KO cells exhibited significantly increased apoptosis due to decreased p53 degradation, likely mediated through Mdm2. Confirming this, enrichment of hypoxic signaling was associated with KRAS inhibitor resistance in a cohort of 31 KRAS\n                    <jats:sup>G12D<\/jats:sup>\n                    cell lines. Our results thus suggest that inhibiting HIF1\u03b1 may sensitize PDAC to radiation and KRAS inhibitors. To explore this, we conducted a drug repurposing screen and identified three HIF1\u03b1 inhibitors (bakuchiol, BAY-87\u20132243, 2-methoxyestradiol) whose sensitivities were correlated with sensitivity to Deltarasin, a KRAS inhibitor. Our findings suggest that HIF1\u03b1 inhibitors could be used to sensitize PDAC to radiotherapy and KRAS inhibitors.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0341912","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T17:35:36Z","timestamp":1774546536000},"page":"e0341912","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["HIF1\u03b1 mediates resistance to radiation and to KRAS inhibitors in pancreatic adenocarcinoma"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0089-3932","authenticated-orcid":true,"given":"Kevin J.","family":"Tu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjit K.","family":"Roy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tami 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