{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T00:20:59Z","timestamp":1792628459389,"version":"4.5.0"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:00:00Z","timestamp":1651104000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"funder":[{"DOI":"10.13039\/501100001809","name":"national natural science foundation of china","doi-asserted-by":"publisher","award":["82072682"],"award-info":[{"award-number":["82072682"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"national natural science foundation of china","doi-asserted-by":"publisher","award":["81802751"],"award-info":[{"award-number":["81802751"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Med Oncol"],"published-print":{"date-parts":[[2022,6]]},"DOI":"10.1007\/s12032-021-01568-w","type":"journal-article","created":{"date-parts":[[2022,4,28]],"date-time":"2022-04-28T00:02:32Z","timestamp":1651104152000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["ERBB2 S310F mutation independently activates PI3K\/AKT and MAPK pathways through homodimers to contribute gallbladder carcinoma growth"],"prefix":"10.1007","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8795-8235","authenticated-orcid":false,"given":"Kun","family":"Fan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheng","family":"Shen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaojian","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijun","family":"Gong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bohao","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wentao","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Suo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoling","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Houbao","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,28]]},"reference":[{"issue":"2018","key":"1568_CR1","doi-asserted-by":"publisher","first-page":"394","DOI":"10.3322\/caac.21492","volume":"68","author":"F Bray","year":"2018","unstructured":"Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A, Global cancer statistics, . GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(2018):394\u2013424.","journal-title":"CA Cancer J Clin"},{"issue":"2019","key":"1568_CR2","doi-asserted-by":"publisher","first-page":"7","DOI":"10.3322\/caac.21551","volume":"69","author":"RL Siegel","year":"2019","unstructured":"Siegel RL, Miller KD, Jemal A. Cancer statistics. CA Cancer J Clin. 2019;69(2019):7\u201334.","journal-title":"CA Cancer J Clin"},{"key":"1568_CR3","doi-asserted-by":"publisher","first-page":"1024","DOI":"10.1136\/gutjnl-2018-316039","volume":"68","author":"M Li","year":"2019","unstructured":"Li M, Liu F, Zhang F, Zhou W, Jiang X, Yang Y, Qu K, Wang Y, Ma Q, Wang T, Bai L, Wang Z, Song X, Zhu Y, Yuan R, Gao Y, Liu Y, Jin Y, Li H, Xiang S, Ye Y, Zhang Y, Jiang L, Hu Y, Hao Y, Lu W, Chen S, Gu J, Zhou J, Gong W, Zhang Y, Wang X, Liu X, Liu C, Liu H, Liu Y, Liu Y. Genomic ERBB2\/ERBB3 mutations promote PD-L1-mediated immune escape in gallbladder cancer: a whole-exome sequencing analysis. Gut. 2019;68:1024\u201333.","journal-title":"Gut"},{"key":"1568_CR4","doi-asserted-by":"publisher","first-page":"75","DOI":"10.3322\/caac.21329","volume":"66","author":"S Roychowdhury","year":"2016","unstructured":"Roychowdhury S, Chinnaiyan AM. Translating cancer genomes and transcriptomes for precision oncology. CA Cancer J Clin. 2016;66:75\u201388.","journal-title":"CA Cancer J Clin"},{"key":"1568_CR5","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1038\/nrm1962","volume":"7","author":"A Citri","year":"2006","unstructured":"Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7:505\u201316.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"1568_CR6","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1038\/s41568-020-00322-0","volume":"21","author":"S Kumagai","year":"2021","unstructured":"Kumagai S, Koyama S, Nishikawa H. Antitumour immunity regulated by aberrant ERBB family signalling. Nat Rev Cancer. 2021;21:181\u201397.","journal-title":"Nat Rev Cancer"},{"key":"1568_CR7","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1038\/35052073","volume":"2","author":"Y Yarden","year":"2001","unstructured":"Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 2001;2:127\u201337.","journal-title":"Nat Rev Mol Cell Biol"},{"key":"1568_CR8","doi-asserted-by":"publisher","first-page":"792","DOI":"10.1016\/j.ccell.2018.09.010","volume":"34","author":"KB Pahuja","year":"2018","unstructured":"Pahuja KB, Nguyen TT, Jaiswal BS, Prabhash K, Thaker TM, Senger K, Chaudhuri S, Kljavin NM, Antony A, Phalke S, Kumar P, Mravic M, Stawiski EW, Vargas D, Durinck S, Gupta R, Khanna-Gupta A, Trabucco SE, Sokol ES, Hartmaier RJ, Singh A, Chougule A, Trivedi V, Dutt A, Patil V, Joshi A, Noronha V, Ziai J, Banavali SD, Ramprasad V, DeGrado WF, Bueno R, Jura N, Seshagiri S. Actionable Activating Oncogenic ERBB2\/HER2 transmembrane and juxtamembrane domain mutations. Cancer Cell. 2018;34:792\u2013806.","journal-title":"Cancer Cell"},{"key":"1568_CR9","doi-asserted-by":"publisher","first-page":"414","DOI":"10.1016\/j.jtho.2015.10.025","volume":"11","author":"BT Li","year":"2016","unstructured":"Li BT, Ross DS, Aisner DL, Chaft JE, Hsu M, Kako SL, Kris MG, Varella-Garcia M, Arcila ME. HER2 amplification and HER2 mutation are distinct molecular targets in lung cancers. J Thorac Oncol. 2016;11:414\u20139.","journal-title":"J Thorac Oncol"},{"key":"1568_CR10","doi-asserted-by":"publisher","first-page":"4619","DOI":"10.3748\/wjg.v22.i19.4619","volume":"22","author":"LF Abrahao-Machado","year":"2016","unstructured":"Abrahao-Machado LF, Scapulatempo-Neto C. HER2 testing in gastric cancer: An update. World J Gastroenterol. 2016;22:4619\u201325.","journal-title":"World J Gastroenterol"},{"key":"1568_CR11","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1016\/S1470-2045(18)30405-4","volume":"19","author":"L Gianni","year":"2018","unstructured":"Gianni L. Is there room for another HER2-targeting drug? Lancet Oncol. 2018;19:847\u20139.","journal-title":"Lancet Oncol"},{"key":"1568_CR12","doi-asserted-by":"publisher","first-page":"14476","DOI":"10.1073\/pnas.1203201109","volume":"109","author":"H Greulich","year":"2012","unstructured":"Greulich H, Kaplan B, Mertins P, Chen TH, Tanaka KE, Yun CH, Zhang X, Lee SH, Cho J, Ambrogio L, Liao R, Imielinski M, Banerji S, Berger AH, Lawrence MS, Zhang J, Pho NH, Walker SR, Winckler W, Getz G, Frank D, Hahn WC, Eck MJ, Mani DR, Jaffe JD, Carr SA, Wong KK, Meyerson M. Functional analysis of receptor tyrosine kinase mutations in lung cancer identifies oncogenic extracellular domain mutations of ERBB2. Proc Natl Acad Sci U S A. 2012;109:14476\u201381.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"1568_CR13","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1038\/s41388-019-1001-5","volume":"39","author":"N Kiavue","year":"2020","unstructured":"Kiavue N, Cabel L, Melaabi S, Bataillon G, Callens C, Lerebours F, Pierga JY, Bidard FC. ERBB3 mutations in cancer: biological aspects, prevalence and therapeutics. Oncogene. 2020;39:487\u2013502.","journal-title":"Oncogene"},{"key":"1568_CR14","doi-asserted-by":"publisher","first-page":"5903","DOI":"10.1002\/cam4.2463","volume":"8","author":"K Fan","year":"2019","unstructured":"Fan K, Fan Z, Cheng H, Huang Q, Yang C, Jin K, Luo G, Yu X, Liu C. Hexokinase 2 dimerization and interaction with voltage-dependent anion channel promoted resistance to cell apoptosis induced by gemcitabine in pancreatic cancer. Cancer Med. 2019;8:5903\u201315.","journal-title":"Cancer Med"},{"key":"1568_CR15","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1002\/cncr.31850","volume":"125","author":"RR Narayan","year":"2019","unstructured":"Narayan RR, Creasy JM, Goldman DA, Gonen M, Kandoth C, Kundra R, Solit DB, Askan G, Klimstra DS, Basturk O, Allen PJ, Balachandran VP, D\u2019Angelica MI, DeMatteo RP, Drebin JA, Kingham TP, Simpson AL, Abou-Alfa GK, Harding JJ, O\u2019Reilly EM, Butte JM, Matsuyama R, Endo I, Jarnagin WR. Regional differences in gallbladder cancer pathogenesis: Insights from a multi-institutional comparison of tumor mutations. Cancer. 2019;125:575\u201385.","journal-title":"Cancer"},{"key":"1568_CR16","doi-asserted-by":"publisher","first-page":"872","DOI":"10.1038\/ng.3030","volume":"46","author":"M Li","year":"2014","unstructured":"Li M, Zhang Z, Li X, Ye J, Wu X, Tan Z, Liu C, Shen B, Wang XA, Wu W, Zhou D, Zhang D, Wang T, Liu B, Qu K, Ding Q, Weng H, Ding Q, Mu J, Shu Y, Bao R, Cao Y, Chen P, Liu T, Jiang L, Hu Y, Dong P, Gu J, Lu W, Shi W, Lu J, Gong W, Tang Z, Zhang Y, Wang X, Chin YE, Weng X, Zhang H, Tang W, Zheng Y, He L, Wang H, Liu Y, Liu Y. Whole-exome and targeted gene sequencing of gallbladder carcinoma identifies recurrent mutations in the ErbB pathway. Nat Genet. 2014;46:872\u20136.","journal-title":"Nat Genet"},{"key":"1568_CR17","first-page":"541","volume":"12","author":"AW Burgess","year":"2003","unstructured":"Burgess AW, Cho HS, Eigenbrot C, Ferguson KM, Garrett TP, Leahy DJ, Lemmon MA, Sliwkowski MX, Ward CW, Yokoyama S. An open-and-shut case? Recent insights into the activation of EGF\/ErbB receptors, Mol Cell. 2003;12:541\u201352.","journal-title":"Recent insights into the activation of EGF\/ErbB receptors, Mol Cell"},{"key":"1568_CR18","doi-asserted-by":"publisher","first-page":"563","DOI":"10.1007\/s00418-008-0401-3","volume":"129","author":"K Roepstorff","year":"2008","unstructured":"Roepstorff K, Grovdal L, Grandal M, Lerdrup M, van Deurs B. Endocytic downregulation of ErbB receptors: mechanisms and relevance in cancer. Histochem Cell Biol. 2008;129:563\u201378.","journal-title":"Histochem Cell Biol"},{"key":"1568_CR19","doi-asserted-by":"publisher","first-page":"6742","DOI":"10.1158\/1078-0432.CCR-19-1398","volume":"25","author":"M Ponz-Sarvise","year":"2019","unstructured":"Ponz-Sarvise M, Corbo V, Tiriac H, Engle DD, Frese KK, Oni TE, Hwang CI, Ohlund D, Chio IIC, Baker LA, Filippini D, Wright K, Bapiro TE, Huang P, Smith P, Yu KH, Jodrell DI, Park Y, Tuveson DA. Identification of resistance pathways specific to malignancy using organoid models of pancreatic cancer. Clin Cancer Res. 2019;25:6742\u201355.","journal-title":"Clin Cancer Res"},{"key":"1568_CR20","doi-asserted-by":"crossref","unstructured":"J. Zhou, T. Du, B. Li, Y. Rong, A. Verkhratsky, L. Peng, Crosstalk Between MAPK\/ERK and PI3K\/AKT Signal Pathways During Brain Ischemia\/Reperfusion, ASN Neuro, 7 (2015).","DOI":"10.1177\/1759091415602463"},{"key":"1568_CR21","doi-asserted-by":"publisher","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","volume":"144","author":"D Hanahan","year":"2011","unstructured":"Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646\u201374.","journal-title":"Cell"},{"key":"1568_CR22","doi-asserted-by":"publisher","first-page":"703","DOI":"10.1016\/j.cell.2008.08.021","volume":"134","author":"PP Hsu","year":"2008","unstructured":"Hsu PP, Sabatini DM. Cancer cell metabolism: Warburg and beyond. Cell. 2008;134:703\u20137.","journal-title":"Cell"},{"key":"1568_CR23","doi-asserted-by":"publisher","first-page":"498","DOI":"10.1038\/s41556-019-0299-0","volume":"21","author":"F Chen","year":"2019","unstructured":"Chen F, Chen J, Yang L, Liu J, Zhang X, Zhang Y, Tu Q, Yin D, Lin D, Wong PP, Huang D, Xing Y, Zhao J, Li M, Liu Q, Su F, Su S, Song E. Extracellular vesicle-packaged HIF-1alpha-stabilizing lncRNA from tumour-associated macrophages regulates aerobic glycolysis of breast cancer cells. Nat Cell Biol. 2019;21:498\u2013510.","journal-title":"Nat Cell Biol"},{"key":"1568_CR24","doi-asserted-by":"publisher","first-page":"6093","DOI":"10.1038\/sj.onc.1203967","volume":"19","author":"PJ Brennan","year":"2000","unstructured":"Brennan PJ, Kumagai T, Berezov A, Murali R, Greene MI. HER2\/neu: mechanisms of dimerization\/oligomerization. Oncogene. 2000;19:6093\u2013101.","journal-title":"Oncogene"},{"key":"1568_CR25","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.phrs.2013.11.002","volume":"79","author":"R Roskoski Jr","year":"2014","unstructured":"Roskoski R Jr. The ErbB\/HER family of protein-tyrosine kinases and cancer. Pharmacol Res. 2014;79:34\u201374.","journal-title":"Pharmacol Res"},{"key":"1568_CR26","doi-asserted-by":"publisher","first-page":"5867","DOI":"10.1038\/s41388-020-01404-x","volume":"39","author":"T Maeda","year":"2020","unstructured":"Maeda T, Kitamura S, Nishihara H, Yanagi T. Extramammary Paget\u2019s disease patient-derived xenografts harboring ERBB2 S310F mutation show sensitivity to HER2-targeted therapies. Oncogene. 2020;39:5867\u201375.","journal-title":"Oncogene"},{"key":"1568_CR27","doi-asserted-by":"crossref","unstructured":"J.W. Shin, S. Kim, S. Ha, B. Choi, S. Kim, S.A. Im, T.Y. Yoon, J. Chung, The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as well as Pertuzumab, Biomolecules, 9 (2019).","DOI":"10.3390\/biom9100629"},{"key":"1568_CR28","doi-asserted-by":"publisher","first-page":"5687","DOI":"10.1158\/1078-0432.CCR-17-0900","volume":"23","author":"CX Ma","year":"2017","unstructured":"Ma CX, Bose R, Gao F, Freedman RA, Telli ML, Kimmick G, Winer E, Naughton M, Goetz MP, Russell C, Tripathy D, Cobleigh M, Forero A, Pluard TJ, Anders C, Niravath PA, Thomas S, Anderson J, Bumb C, Banks KC, Lanman RB, Bryce R, Lalani AS, Pfeifer J, Hayes DF, Pegram M, Blackwell K, Bedard PL, Al-Kateb H, Ellis MJC. Neratinib efficacy and circulating tumor DNA detection of HER2 mutations in HER2 nonamplified metastatic breast cancer. Clin Cancer Res. 2017;23:5687\u201395.","journal-title":"Clin Cancer Res"}],"container-title":["Medical Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-021-01568-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12032-021-01568-w\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12032-021-01568-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,1]],"date-time":"2022-06-01T01:19:49Z","timestamp":1654046389000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12032-021-01568-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,4,28]]},"references-count":28,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2022,6]]}},"alternative-id":["1568"],"URL":"https:\/\/doi.org\/10.1007\/s12032-021-01568-w","relation":{},"ISSN":["1559-131X"],"issn-type":[{"value":"1559-131X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,4,28]]},"assertion":[{"value":"3 June 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 April 2022","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no conflicts of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of Interest"}},{"value":"All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and\/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"64"}}