{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T18:19:40Z","timestamp":1791483580770,"version":"4.3.4"},"reference-count":54,"publisher":"National Academy of Sciences","issue":"4","license":[{"start":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T00:00:00Z","timestamp":1768953600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,1,27]]},"abstract":"<jats:p>\n                    Activation of transcription factor NRF2 in pancreatic ductal adenocarcinoma (PDAC) promotes aggressive tumor phenotype and protection from therapy-induced oxidative stress. We postulated that NRF2\n                    <jats:sup>high<\/jats:sup>\n                    PDAC can be selectively targeted by C29h, a prodrug that is activated by the NRF2-induced enzyme NAD(P)H:quinone oxidoreductase-1 (NQO1), which is elevated in human pancreatic tumors. Initial evaluations of C29h alone or together with the standard-of-care chemotherapeutic drug gemcitabine were conducted on NQO1\n                    <jats:sup>high<\/jats:sup>\n                    human and mouse PDAC cell lines and patient-derived organoids. As PDAC is enriched in collagen-containing extracellular matrix (ECM) that activates NRF2 and induces NQO1 expression, we examined the ECM effect on the response to C29h, as well as in vivo tumor control in IKK\u03b1-deficient\n                    <jats:italic toggle=\"yes\">\n                      Kras\n                      <jats:sup>G12D<\/jats:sup>\n                      \/Ikk\u03b1\n                      <jats:sup>\u0394PEC<\/jats:sup>\n                    <\/jats:italic>\n                    mice in which NRF2 is strongly activated, immunocompromised\n                    <jats:italic toggle=\"yes\">Nu\/Nu<\/jats:italic>\n                    mice orthotopically transplanted with human PDAC cells and C57BL\/6n and NOD\/SCID mice transplanted with mouse PDAC. C29h led to NQO1-dependent killing of human and mouse PDAC cell lines and organoids and acted additively with gemcitabine. Furthermore, ECM-plated PDAC cells were more susceptible to C29h cytotoxicity than cells grown on plastic. Importantly, C29h treatment induced tumor regression and increased the survival of PDAC-bearing mice and optimal C29h-induced tumor regression was dependent on CD8\n                    <jats:sup>+<\/jats:sup>\n                    T lymphocytes whose tumoral recruitment was enhanced by drug treatment. This study supports the use of C29h alone or as part of a drug combination as an effective and promising strategy for selective eradication of NRF2\n                    <jats:sup>high<\/jats:sup>\n                    PDAC.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2511733123","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T18:45:37Z","timestamp":1769021137000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":3,"title":["Selective targeting of NRF2-high pancreatic ductal adenocarcinoma with an NQO1-activatable prodrug"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3659-7334","authenticated-orcid":false,"given":"Laura","family":"Antonucci","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]},{"name":"Department of Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0260-2323","authenticated-orcid":false,"given":"Kosuke","family":"Watari","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]},{"name":"Department of Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yechen","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]},{"name":"Department of Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Qi","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]},{"name":"Department of Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mandy","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]},{"name":"Department of Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tingya","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, Southeast University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Ng","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily A.","family":"Vucic","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irene","family":"Riahi","sequence":"additional","affiliation":[{"name":"Department of Pathology, Jonsson Cancer Center, University of California Los Angeles David Geffen School of Medicine","place":["Los Angeles"]},{"name":"Department of Laboratory Medicine, Jonsson Cancer Center, University of California Los Angeles David Geffen School of Medicine","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, The First Affiliated Hospital, Zhejiang University School of Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojgan","family":"Hosseini","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evangeline","family":"Mose","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Randall","family":"French","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Weitz","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dafna","family":"Bar-Sagi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0215-5861","authenticated-orcid":false,"given":"David W.","family":"Dawson","sequence":"additional","affiliation":[{"name":"Department of Pathology, Jonsson Cancer Center, University of California Los Angeles David Geffen School of Medicine","place":["Los Angeles"]},{"name":"Department of Laboratory Medicine, Jonsson Cancer Center, University of California Los Angeles David Geffen School of Medicine","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beicheng","family":"Sun","sequence":"additional","affiliation":[{"name":"Department of Hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Herve","family":"Tiriac","sequence":"additional","affiliation":[{"name":"Moores Cancer Center, University of California San Diego","place":["La Jolla"]},{"name":"Department of Surgery, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyi","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shengtao","family":"Xu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew M.","family":"Lowy","sequence":"additional","affiliation":[{"name":"Department of Surgery, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2758-6473","authenticated-orcid":false,"given":"Michael","family":"Karin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]},{"name":"Department of Pathology, Laboratory of Gene Regulation and Signal Transduction, University of California San Diego School of Medicine","place":["La Jolla"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,1,21]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.34479"},{"key":"e_1_3_4_2_2","unstructured":"National Cancer Institute Surveillance Epidemiology and End Results Program. https:\/\/seer.cancer.gov\/statistics-network\/explorer\/. Accessed 7 December 2023."},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14102417"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1200\/EDBK_397082"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgn095"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01704-07"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2021.05.016"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.10.011"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2012.05.016"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.18632\/genesandcancer.171"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-022-05169-z"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-025-01003-3"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986708785132997"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.0c00082"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2021.101950"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0891-5849(00)00310-5"},{"key":"e_1_3_4_17_2","first-page":"5175","article-title":"Effect of the Nrf2-ARE signaling pathway on biological characteristics and sensitivity to sunitinib in renal cell carcinoma","volume":"17","author":"Ji S.","year":"2019","unstructured":"S. Ji, Y. Xiong, X. Zhao, Y. Liu, L. Q. Yu, Effect of the Nrf2-ARE signaling pathway on biological characteristics and sensitivity to sunitinib in renal cell carcinoma. Oncol. Lett. 17, 5175\u20135186 (2019).","journal-title":"Oncol. Lett."},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.lfs.2015.12.017"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.3389\/fcell.2023.1174535"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-09-3237"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1021\/acs.bioconjchem.6b00184"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejmech.2017.03.055"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.2056"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/fsn3.3986"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41418-020-0496-1"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1097\/PAI.0b013e31802e91d0"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2344"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1038\/ng.3398"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature16965"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2020.05.013"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature17988"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2953"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2021.02.016"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/bs.acr.2023.02.010"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2023.12.002"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2023.08.003"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-18-0349"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1038\/s42003-024-06087-8"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1320318110"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1717802115"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080580"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1720948115"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-14-2921"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2016-312078"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-023-33508-1"},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature10189"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1042\/bj20030754"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cgh.2009.07.039"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.152761"},{"key":"e_1_3_4_50_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11238-1"},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk1827"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.devcel.2023.07.025"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.594609"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41416-020-01048-4"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2511733123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T18:45:46Z","timestamp":1769021146000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2511733123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,21]]},"references-count":54,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,1,27]]}},"alternative-id":["10.1073\/pnas.2511733123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2511733123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,21]]},"assertion":[{"value":"2025-05-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-01-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2511733123"}}