{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,24]],"date-time":"2026-08-24T23:35:06Z","timestamp":1787614506840,"version":"build-2736575974"},"reference-count":16,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T00:00:00Z","timestamp":1748217600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100008891","name":"Loma Linda University","doi-asserted-by":"publisher","award":["Research Innovation Grant"],"award-info":[{"award-number":["Research Innovation Grant"]}],"id":[{"id":"10.13039\/100008891","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008891","name":"Loma Linda University","doi-asserted-by":"publisher","award":["GRASP"],"award-info":[{"award-number":["GRASP"]}],"id":[{"id":"10.13039\/100008891","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Exp Hematol Oncol"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:p>Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy with a 5-year overall survival (OS) rate of approximately 12%. More than 90% of PDAC patients harbor oncogenic mutations in the Kirsten rat sarcoma viral homolog (<jats:italic>KRAS)<\/jats:italic> gene. MRTX1133 (MRTX), a novel inhibitor of <jats:italic>KRAS<\/jats:italic>\n            <jats:sup>\n              <jats:italic>G12D<\/jats:italic>\n            <\/jats:sup> (the most common <jats:italic>KRAS<\/jats:italic> mutation found in pancreatic and colon cancers) has shown promise as a therapeutic agent. To address reported resistance to MRTX, we adapted our anti-leukemia co-targeting strategy and evaluated a combination of MRTX and Bedaquiline (BED), an FDA-approved inhibitor of mitochondrial ATP production, in in vitro human PDAC models. The combination of MRTX and BED demonstrated enhanced cytotoxic effects by disrupting all 11 genes within the DNA helicase family (CMG complex: <jats:italic>CDC45-MCM-GINS<\/jats:italic>), which are essential for initiating DNA replication and regulating cell cycle progression. Notably, real-world data analysis from Caris Life Sciences and NCI-TCGA database revealed that low transcriptomic expression of the DNA helicase CMG complex was significantly associated with prolonged survival (e.g., low <jats:italic>CDC45<\/jats:italic> expression and low <jats:italic>GINS2<\/jats:italic> expression with greater than 8 months longer overall survival) in PDAC patients with <jats:italic>KRAS<\/jats:italic>\n            <jats:sup>\n              <jats:italic>G12<\/jats:italic>\n            <\/jats:sup> mutations (<jats:italic>N<\/jats:italic>\u2009=\u20099,717; <jats:italic>P<\/jats:italic>\u2009&lt;\u20090.00001). However, this combination therapy also triggered strong pro-survival nuclear reprogramming. This effect was mediated by significant genetic activation of an NF\u03baB2-DDIT (DNA damage-induced transcript) axis, which supported tumor chromosomal integrity and DNA repair mechanisms. To overcome NF\u03baB2-driven resistance mechanisms, we explored a triple-targeting strategy that addresses metabolic and genomic plasticity in addition to actively intercepting cell division. This approach combines MRTX1133, Bedaquiline, and the NF\u03baB2 inhibitor SN52, offering a novel therapeutic avenue to treat aggressive pancreatic cancer and potentially improve patient outcomes.<\/jats:p>","DOI":"10.1186\/s40164-025-00669-w","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T03:46:36Z","timestamp":1748231196000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Targeting DNA helicase CMG complex and NF\u03baB2-driven drug-resistant transcriptional axis to effectively treat KRASG12D-mutated pancreatic cancer"],"prefix":"10.1186","volume":"14","author":[{"given":"Jeffrey","family":"Xiao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandon","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David J.","family":"Baylink","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cedric","family":"Kwon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Tran","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Scott","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Codorniz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laren","family":"Tan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pamela Lobo","family":"Moreno","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Schill-Depew","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saied","family":"Mirshahidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"De Semir","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Hanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiran","family":"Naqvi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huynh","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Shing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joanne","family":"Xiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heinz-Josef","family":"Lenz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hamid","family":"Mirshahidi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark E","family":"Reeves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"key":"669_CR1","doi-asserted-by":"publisher","first-page":"12","DOI":"10.3322\/caac.21820","volume":"74","author":"RL Siegel","year":"2024","unstructured":"Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12\u201349. https:\/\/doi.org\/10.3322\/caac.21820.","journal-title":"CA Cancer J Clin"},{"key":"669_CR2","doi-asserted-by":"publisher","first-page":"2969","DOI":"10.1158\/0008-5472.CAN-19-3682","volume":"80","author":"IA Prior","year":"2020","unstructured":"Prior IA, Hood FE, Hartley JL. The frequency of Ras mutations in Cancer. Cancer Res. 2020;80:2969\u201374. https:\/\/doi.org\/10.1158\/0008-5472.CAN-19-3682.","journal-title":"Cancer Res"},{"key":"669_CR3","doi-asserted-by":"publisher","first-page":"1605","DOI":"10.1056\/NEJMra0901557","volume":"362","author":"M Hidalgo","year":"2010","unstructured":"Hidalgo M. Pancreatic cancer. N Engl J Med. 2010;362:1605\u201317. https:\/\/doi.org\/10.1056\/NEJMra0901557.","journal-title":"N Engl J Med"},{"key":"669_CR4","doi-asserted-by":"publisher","unstructured":"Xu Y, et al. 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The other authors declare no potential conflicts of interest related to this study.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"79"}}