{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T22:11:04Z","timestamp":1791583864880,"version":"4.3.4"},"reference-count":49,"publisher":"National Academy of Sciences","issue":"44","license":[{"start":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T00:00:00Z","timestamp":1761609600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82125037"],"award-info":[{"award-number":["82125037"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"MOST | National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82273153"],"award-info":[{"award-number":["82273153"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012166","name":"MOST | National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2308200"],"award-info":[{"award-number":["2023YFC2308200"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Jiangsu Provincial Medical Innovation Center","award":["CXZX202225"],"award-info":[{"award-number":["CXZX202225"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,11,4]]},"abstract":"<jats:p>Receptor tyrosine kinase pathway rewiring represents a fundamental mechanism underlying acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small-cell lung cancer (NSCLC). While posttranslational modifications facilitate aberrant activation of bypass signaling networks, the specific contribution of ZDHHC palmitoyl acyltransferase-mediated palmitoylation remains poorly characterized. Here, ZDHHC11-mediated palmitoylation contributes to osimertinib resistance in EGFR-mutant NSCLC. Patient samples, along with in vitro and in vivo functional studies, indicated that ZDHHC11 upregulation reduces the sensitivity of tumor cells to osimertinib by promoting malignant phenotype. Mechanistically, we establish AXL receptor tyrosine kinase as the critical substrate. ZDHHC11 catalyzes AXL palmitoylation at Cys869, inducing plasma membrane retention and constitutive activation. This triggers downstream PI3K\u2013AKT signaling, with AXL knockout alleviating the effect of ZDHHC11-driven resistance. Crucially, pharmacological inhibition ZDHHC11-mediated palmitoylation with the broad-spectrum palmitoylation inhibitor 2-bromopalmitate effectively augmented the antitumor effects of osimertinib. Collectively, ZDHHC11 regulates osimertinib resistance in a palmitoylation-dependent manner. Targeting the ZDHHC11\u2013AXL axis may provide a promising therapeutic strategy for the treatment of osimertinib-resistant EGFR-mutant NSCLC patients with high ZDHHC11 expression.<\/jats:p>","DOI":"10.1073\/pnas.2502778122","type":"journal-article","created":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:39:01Z","timestamp":1761673141000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":13,"title":["ZDHHC11-mediated AXL palmitoylation promotes osimertinib resistance in non-small-cell lung cancer"],"prefix":"10.1073","volume":"122","author":[{"given":"He","family":"Cui","sequence":"first","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-7667-7497","authenticated-orcid":false,"given":"Xueting","family":"Cai","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Medicinal Innovation Center, Jiangsu Province Academy of Traditional Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Qian","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuyuan","family":"Fan","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tian","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Wang","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixuan","family":"Dai","sequence":"additional","affiliation":[{"name":"Department of Radiology, The First Affiliated Hospital of Nanjing Medical University","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yunwei","family":"Song","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Medicinal Innovation Center, Jiangsu Province Academy of Traditional Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Sun","sequence":"additional","affiliation":[{"name":"Jiangsu Provincial Medicinal Innovation Center, Jiangsu Province Academy of Traditional Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2044-3074","authenticated-orcid":false,"given":"Peng","family":"Cao","sequence":"additional","affiliation":[{"name":"Jiangsu Key Laboratory for Pharmacology and Safety Research of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"State Key Laboratory on Technologies for Chinese Medicine Pharmaceutical Process Control and Intelligent Manufacture, Nanjing University of Chinese Medicine","place":["Nanjing, China"]},{"name":"Jiangsu Provincial Medicinal Innovation Center, Jiangsu Province Academy of Traditional Chinese Medicine","place":["Nanjing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2025,10,28]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.21.01626"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2019.09.015"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13045-022-01391-4"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMe1714580"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdx704"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-021-00195-8"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-018-0777-1"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.critrevonc.2024.104295"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2018.09.004"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-022-00337-w"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2022.11.022"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2018.05.003"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2084"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2018.07.034"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.R600007-JLR200"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10555-024-10217-3"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.3390\/cells12182209"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.72244"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/1541-7786.MCR-14-0608"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11626-023-00755-5"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cancergencyto.2007.12.004"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41573-023-00846-8"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14030466"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.humpath.2015.08.014"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-023-02726-w"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08074-0"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.2010.515980"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.03.010"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-024-00700-8"},{"key":"e_1_3_4_30_2","first-page":"295","article-title":"Effects of repeated anesthesia containing urethane on tumor formation and health scores in male C57BL\/6J mice","volume":"55","author":"Rex T. S.","year":"2016","unstructured":"T. S. Rex , Effects of repeated anesthesia containing urethane on tumor formation and health scores in male C57BL\/6J mice. J. Am. Assoc. Lab. Anim. Sci. 55, 295\u2013299 (2016).","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1417406"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.taap.2021.115518"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2799-2"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2023.104965"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-04075-0"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1038\/d41586-023-00538-8"},{"key":"e_1_3_4_37_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1224125"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1337478"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2016.04.003"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.aax2364"},{"key":"e_1_3_4_41_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41401-024-01237-4"},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1111\/cas.15608"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-1558"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2016.428"},{"key":"e_1_3_4_45_2","first-page":"1821","article-title":"Activation of AXL and antitumor effects of a monoclonal antibody to AXL in lung adenocarcinoma","volume":"34","author":"Iida S.","year":"2014","unstructured":"S. Iida , Activation of AXL and antitumor effects of a monoclonal antibody to AXL in lung adenocarcinoma. Anticancer Res. 34, 1821\u20131827 (2014).","journal-title":"Anticancer Res."},{"key":"e_1_3_4_46_2","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.70544"},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2022.111194"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.811247"},{"key":"e_1_3_4_49_2","first-page":"530","article-title":"Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6. Cell","volume":"29","author":"Qiu N.","year":"2022","unstructured":"N. Qiu , Artemisinin inhibits NRas palmitoylation by targeting the protein acyltransferase ZDHHC6. Cell. Chem. Biol. 29, 530\u2013537.e7 (2022).","journal-title":"Chem. Biol."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2502778122","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,28]],"date-time":"2025-10-28T17:39:03Z","timestamp":1761673143000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2502778122"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,28]]},"references-count":49,"journal-issue":{"issue":"44","published-print":{"date-parts":[[2025,11,4]]}},"alternative-id":["10.1073\/pnas.2502778122"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2502778122","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,28]]},"assertion":[{"value":"2025-02-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-09-08","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-28","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2502778122"}}