{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:22:39Z","timestamp":1792729359515,"version":"4.5.0"},"reference-count":47,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T00:00:00Z","timestamp":1736208000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>\n                    As an antibody-drug conjugate (ADC), disitamab vedotin (RC48) is a promising treatment targeting ERBB2 for locally advanced and metastatic bladder cancer (BLCA). However, the subtype heterogeneity of muscle-invasive bladder cancer (MIBC) often leads to different therapeutic outcomes. In our study, we aim to explore sensitivity differences and mechanisms of different molecular subtypes of MIBC to RC48 treatment and develop a strategy for combination therapy against cancer. Using large-scale mRNA expression profile datasets, Western blotting, and immunohistochemistry, we first found that ERBB2 is upregulated in the luminal type but downregulated in basal bladder cancer. In addition, luminal cells showed higher sensitivity to RC48 than basal cells. Basal cells with ERBB2 overexpression demonstrated increased sensitivity to RC48\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    , indicating that ERBB2 expression mediates RC48\u2019s therapeutic efficacy against cancer. In basal or RC48-exposed luminal cells, the JAK\/STAT3 pathway was highly enriched, suggesting that downregulation or pharmacological inhibition of ERBB2 leads to compensatory activation of this pathway. Silencing STAT3 increased the inhibitory efficacy of RC48. In addition, artesunate (ART, a STAT3 inhibitor) showed a synergistic effect with RC48 against basal bladder cancer both\n                    <jats:italic>in vitro<\/jats:italic>\n                    and\n                    <jats:italic>in vivo<\/jats:italic>\n                    . In summary, these findings provide a theoretical foundation for subsequent clinical trials combining RC48 and ART in MIBC based on molecular subtypes.\n                  <\/jats:p>","DOI":"10.3389\/fimmu.2024.1432586","type":"journal-article","created":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T02:47:11Z","timestamp":1736218031000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["The combination treatment of RC48 and STAT3 inhibitor acts as a promising therapeutic strategy for basal bladder cancer"],"prefix":"10.3389","volume":"15","author":[{"given":"Jingxian","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Shan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiang","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjiong","family":"Qi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihong","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianqiang","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E.","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,7]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"58","DOI":"10.1038\/s41572-023-00468-9","article-title":"Bladder cancer","volume":"9","author":"Lars","year":"2023","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(16)30512-8","article-title":"Bladder cancer","volume":"388","author":"Kamat","year":"2016","journal-title":"Lancet (London England)"},{"key":"B3","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.eururo.2020.03.055","article-title":"European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2020 guidelines","volume":"79","author":"Witjes","year":"2021","journal-title":"Eur Urol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/s0140-6736(20)30230-0","article-title":"Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial","volume":"395","author":"Galsky","year":"2020","journal-title":"Lancet (London England)"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2023.08.016","article-title":"European association of urology guidelines on muscle-invasive and metastatic bladder cancer: summary of the 2023 guidelines","volume":"85","author":"AW","year":"2023","journal-title":"Eur Urol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2312117","article-title":"Enfortumab vedotin and pembrolizumab in untreated advanced urothelial cancer","volume":"390","author":"Thomas","year":"2024","journal-title":"N Engl J Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1200\/jco.20.03489","article-title":"TROPHY-U-01: A phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors","volume":"39","author":"Tagawa","year":"2021","journal-title":"J Clin Oncol"},{"key":"B8","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.3390\/ijms20051115","article-title":"HER2 directed antibody-drug-conjugates beyond T-DM1 in breast cancer","volume":"20","author":"Rinnerthaler","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1002\/cac2.12214","article-title":"Efficacy and safety of a novel anti-HER2 therapeutic antibody RC48 in patients with HER2-overexpressing, locally advanced or metastatic gastric or gastroesophageal junction cancer: a single-arm phase II study","volume":"41","author":"Peng","year":"2021","journal-title":"Cancer Commun (London England)"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.esmoop.2022.100395","article-title":"Consensus for HER2 alterations testing in non-small-cell lung cancer","volume":"7","author":"Ren","year":"2022","journal-title":"ESMO Open"},{"key":"B11","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1158\/1078-0432.Ccr-20-2488","article-title":"Open-label, multicenter, phase II study of RC48-ADC, a HER2-targeting antibody\u2013drug conjugate, in patients with locally advanced or metastatic urothelial carcinoma","volume":"27","author":"Sheng","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.eururo.2019.09.006","article-title":"A consensus molecular classification of muscle-invasive bladder cancer","volume":"77","author":"Kamoun","year":"2020","journal-title":"Eur Urol"},{"key":"B13","doi-asserted-by":"publisher","first-page":"9743","DOI":"10.1038\/s41598-020-66747-7","article-title":"Assessment of luminal and basal phenotypes in bladder cancer","volume":"10","author":"Guo","year":"2020","journal-title":"Sci Rep"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.Ccr-20-4175","article-title":"NECTIN4Heterogeneity in expression across molecular subtypes of urothelial cancer mediates sensitivity to enfortumab vedotin","volume":"27","author":"Chu","year":"2021","journal-title":"Clin Cancer Res"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.euo.2021.11.005","article-title":"TROP2 expression across molecular subtypes of urothelial carcinoma and enfortumab vedotin-resistant cells","volume":"5","author":"Chou","year":"2022","journal-title":"Eur Urol Oncol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"564","DOI":"10.1016\/j.cell.2017.06.010","article-title":"Defining a cancer dependency map","volume":"170","author":"Tsherniak","year":"2017","journal-title":"Cell"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.33794","article-title":"Single-cell RNA sequencing reveals the epithelial cell heterogeneity and invasive subpopulation in human bladder cancer","volume":"149","author":"Lai","year":"2021","journal-title":"Int J Cancer"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1000412","article-title":"Improving bioscience research reporting: the ARRIVE guidelines for reporting animal research","volume":"8","author":"Carol","year":"2010","journal-title":"PloS Biol"},{"key":"B19","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/j.eururo.2021.09.026","article-title":"The 2021 updated European association of urology guidelines on metastatic urothelial carcinoma","volume":"81","author":"Cathomas","year":"2022","journal-title":"Eur Urol"},{"key":"B20","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1038\/s41467-017-02391-6","article-title":"Perturbation-response genes reveal signaling footprints in cancer gene expression","volume":"9","author":"Schubert","year":"2018","journal-title":"Nat Commun"},{"key":"B21","doi-asserted-by":"publisher","first-page":"1219","DOI":"10.3390\/cancers11091219","article-title":"Hyper-activation of STAT3 sustains progression of non-papillary basal-type bladder cancer via FOSL1 regulome","volume":"11","author":"Gatta","year":"2019","journal-title":"Cancers"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2016.04.061","article-title":"Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling","volume":"82","author":"Ilamathi","year":"2016","journal-title":"Biomedicine pharmacotherapy = Biomedecine pharmacotherapie"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.phrs.2019.104307","article-title":"Cryptotanshinone protects against pulmonary fibrosis through inhibiting Smad and STAT3 signaling pathways","volume":"147","author":"Zhang","year":"2019","journal-title":"Pharmacol Res"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1080\/14756366.2020.1871336","article-title":"in vitroDesign, synthesis, and evaluation of BP-1-102 analogs with modified hydrophobic fragments for STAT3 inhibition","volume":"36","author":"Oleksak","year":"2021","journal-title":"J Enzyme inhibition medicinal Chem"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41568-020-00313-1","article-title":"Advances in bladder cancer biology and therapy","volume":"21","author":"Tran","year":"2021","journal-title":"Nat Rev Cancer"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/jnci\/djx243","article-title":"Prognostic power of a tumor differentiation gene signature for bladder urothelial carcinomas","volume":"110","author":"Mo","year":"2018","journal-title":"J Natl Cancer Institute"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1318376111","article-title":"Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology","volume":"111","author":"Damrauer","year":"2014","journal-title":"Proc Natl Acad Sci U.S.A"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.01.009","article-title":"Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer with different sensitivities to frontline chemotherapy","volume":"25","author":"Choi","year":"2014","journal-title":"Cancer Cell"},{"key":"B29","doi-asserted-by":"publisher","first-page":"540","DOI":"10.1016\/j.cell.2017.09.007","article-title":"Comprehensive molecular characterization of muscle-invasive bladder cancer","volume":"171","author":"Robertson","year":"2017","journal-title":"Cell"},{"key":"B30","doi-asserted-by":"publisher","first-page":"244ra91","DOI":"10.1126\/scitranslmed.3008970","article-title":"EGFR as a potential therapeutic target for a subset of muscle-invasive bladder cancers presenting a basal-like phenotype","volume":"6","author":"Rebouissou","year":"2014","journal-title":"Sci Trans Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3737","DOI":"10.1038\/s41598-018-22126-x","article-title":"and extended description of the Lund taxonomy for urothelial carcinoma using the TCGA cohort","volume":"8","author":"Marzouka","year":"2018","journal-title":"Sci Rep"},{"key":"B32","article-title":"Expression profiles of ErbB family receptors and prognosis in primary transitional cell carcinoma of the urinary bladder","volume":"7","author":"Chow","year":"2001","journal-title":"Clin Cancer Res"},{"key":"B33","article-title":"Her-2\/neu overexpression in muscle-invasive urothelial carcinoma of the bladder: prognostic significance and comparative analysis in primary and metastatic tumors","volume":"7","author":"Jimenez","year":"2001","journal-title":"Clin Cancer Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.978266","article-title":"Case report: The remarkable response of pembrolizumab combined with RC48 in the third-line treatment of metastatic urothelial carcinoma","volume":"13","author":"Xu","year":"2022","journal-title":"Front Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.Cd-20-0215","article-title":"ERBB2HER2-mediated internalization of cytotoxic agents in amplified or mutant lung cancers","volume":"10","author":"Li","year":"2020","journal-title":"Cancer Discovery"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.urolonc.2021.06.021","article-title":"High expression of ERBB2 is an independent risk factor for reduced recurrence-free survival in patients with stage T1 non-muscle-invasive bladder cancer","volume":"40","author":"Sikic","year":"2022","journal-title":"Urologic Oncol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.05.019","article-title":"Drug resistance via feedback activation of Stat3 in oncogene-addicted cancer cells","volume":"26","author":"Lee","year":"2014","journal-title":"Cancer Cell"},{"key":"B38","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1186\/s13046-019-1161-8","article-title":"Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK\/STAT3\/PD-L1 pathway","volume":"38","author":"Shen","year":"2019","journal-title":"J Exp Clin Cancer research: CR"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.7150\/thno.16827","article-title":"STAT3\/NF-\u03baB-regulated lentiviral TK\/GCV suicide gene therapy for cisplatin-resistant triple-negative breast cancer","volume":"7","author":"Kuo","year":"2017","journal-title":"Theranostics"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.7150\/ijbs.63125","article-title":"Discovery and validation of nitroxoline as a novel STAT3 inhibitor in drug-resistant urothelial bladder cancer","volume":"17","author":"Lin","year":"2021","journal-title":"Int J Biol Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-13-463","article-title":"Efficacy and safety of artemisinin combination therapy (ACT) for non-falciparum malaria: a systematic review","volume":"13","author":"Visser","year":"2014","journal-title":"Malaria J"},{"key":"B42","doi-asserted-by":"publisher","first-page":"CD011547","DOI":"10.1002\/14651858.Cd011547","article-title":"Artemisinin-naphthoquine for treating uncomplicated Plasmodium falciparum malaria","volume":"2015","author":"Isba","year":"2015","journal-title":"Cochrane Database systematic Rev"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3736\/jcim20080206","article-title":"Artesunate combined with vinorelbine plus cisplatin in treatment of advanced non-small cell lung cancer: a randomized controlled trial","volume":"6","author":"Zhang","year":"2008","journal-title":"Zhong xi yi jie he xue bao = J Chin Integr Med"},{"key":"B44","article-title":"First study of oral Artenimol-R in advanced cervical cancer: clinical benefit, tolerability and tumor markers","volume":"31","author":"Jansen","year":"2011","journal-title":"Anticancer Res"},{"key":"B45","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1016\/j.ebiom.2014.11.010","article-title":"A randomised, double blind, placebo-controlled pilot study of oral artesunate therapy for colorectal cancer","volume":"2","author":"Krishna","year":"2015","journal-title":"EBioMedicine"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3109\/00498254.2013.878815","article-title":"Effects of artemisinin antimalarials on Cytochrome P450 enzymes in vitro using recombinant enzymes and human liver microsomes: potential implications for combination therapies","volume":"44","author":"Ericsson","year":"2014","journal-title":"Xenobiotica; fate foreign compounds Biol Syst"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1007\/s00280-016-2960-7","article-title":"Investigation of ototoxicity of artesunate as add-on therapy in patients with metastatic or locally advanced breast cancer: new audiological results from a prospective, open, uncontrolled, monocentric phase I study","volume":"77","author":"K\u00f6nig","year":"2016","journal-title":"Cancer chemotherapy Pharmacol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1432586\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,7]],"date-time":"2025-01-07T02:47:18Z","timestamp":1736218038000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1432586\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,7]]},"references-count":47,"alternative-id":["10.3389\/fimmu.2024.1432586"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1432586","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,7]]},"article-number":"1432586"}}