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Despite its effectiveness, trastuzumab resistance emerges rapidly, driven by molecular alterations including PI3K pathway mutations, signaling cross-talk with estrogen receptors, and overexpression of MUC1, insulin-like growth factor I receptor, among others. This updated review synthesizes molecular mechanisms, summarizes pre-TR and post-TR clinical trials, and analyzes relevant patents, concluding that trastuzumab monotherapy is insufficient for HER2+ disease and supporting future combination strategies.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/trastuzumab-resistance-a-potential-roadblock-for-most-successful-therapy-of-breast-cancer-an-updated-review-of-underlying-mechanisms-clinical-trials-and-patents-to-evade-the-resistance/356874/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/trastuzumab-resistance-a-potential-roadblock-for-most-successful-therapy-of-breast-cancer-an-updated-review-of-underlying-mechanisms-clinical-trials-and-patents-to-evade-the-resistance/356874.png","ImageObject",300,407,{"name":42,"@type":43},"Stanley","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-11-01","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",11,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"为什么曲妥珠单抗在乳腺癌治疗中会出现耐药？","Question",{"text":63,"@type":64},"文中指出，耐药与PI3K通路相关的改变、与雌激素受体的信号交叉、以及MUC1等分子的异常表达有关，从而削弱了曲妥珠单抗阻断HER2介导信号的效果。","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"这篇综述主要从哪些方面梳理曲妥珠单抗耐药？",{"text":68,"@type":64},"综述从分子机制视角总结耐药，并讨论潜在应对策略，同时分析了耐药发生前后（pre-TR与post-TR）时期的临床试验与专利数据。",{"name":70,"@type":61,"acceptedAnswer":71},"作者的总体结论是什么？治疗上未来更倾向哪类方案？",{"text":72,"@type":64},"文章认为曲妥珠单抗单药在HER2阳性乳腺癌治疗中不再适用；更有前景的是联合治疗，例如与帕妥珠单抗等抗体联合，以及联合蛋白激酶抑制剂并靶向如泛素-蛋白酶体通路等机制。","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},356874,1790192584,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,110,115,120,123,127],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":108,"slug":109},7,40,"healthcare",{"id":111,"doc_module":4,"doc_module_name":25,"category_name":112,"show_sort_weight":113,"slug":114},8,"Research & Report",30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":124,"doc_module":4,"doc_module_name":25,"category_name":125,"show_sort_weight":124,"slug":126},10,"Lifestyle","lifestyle",{"id":128,"doc_module":4,"doc_module_name":25,"category_name":129,"show_sort_weight":97,"slug":130},19,"General","general",{"code":4,"msg":82,"data":132},{"doc_id":79,"user_id":133,"nickname":42,"user_avatar":134,"doc_module":4,"category_id":107,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":140,"language":141,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":12,"update_tm":145,"read_time":146},2336477405376,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Review  \nTrastuzumab Resistance, a Potential Roadblock for Most Successful Therapy of Breast Cancer—An Updated Review of Underlying Mechanisms, Clinical Trials and Patents to Evade the Resistance  \nGul Hasan†, Soudipta Pramanik †, Sandhya Singh, Pravin Gurav, Sudha Madhavi Penumaka , Sudheer Kumar and Debabrata Mandal *  \nAcademic Editor: Cristian O. Salas and Felipe AndrésOyarzún-Ampuero  \nReceived: 26 September 2025  \nRevised: 19 November 2025  \nAccepted: 26 November 2025  \nPublished: 22 April 2026  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.  \nDepartment of Biotechnology, National Institute of Pharmaceutical Education and Research, Hajipur 844102, India; gulhasansaifi64@gmail.com (G.H.); pramanik.soudipta@gmail.com (S.P.);  \n[ss5469323@gmail.com](ss5469323@gmail.com) (S.S.); [pravingurav366@gmail.com](pravingurav366@gmail.com) (P.G.); [madhavi47penumaka@gmail.com](madhavi47penumaka@gmail.com) (S.M.P.);  \n[ksudheer093@gmail.com](ksudheer093@gmail.com) (S.K.)  \n* Correspondence: [dmandal@niperhajipur.ac.in](dmandal@niperhajipur.ac.in)[ ](dmandal@niperhajipur.ac.in)† These authors contributed equally to this work.  \nAbstract  \nTrastuzumab is the first humanised monoclonal antibody (Mab) developed for breast cancer (BC) therapy. The high affinity of Trastuzumab Fab-domain binding to the human epidermal growth factor receptor 2 (HER2) receptor, with a K d value of \u003C1 nM, is also accompanied by Fc domain interaction with Fc-receptors in natural killer cells and leukocytes, enabling the killing of tumour cells through antibody-directed cellular cytotoxicity (ADCC) . Trastuzumab blocks the over-expressed HER2 receptor-mediated dimerization and consequent intracellular signalling, leading to cancerous growth. However, the trastuzumab resistance (TR) became the major problem within 1 year of treatment. The mutation in phosphatidylinositol 3′ -kinase (PI3K) pathway, cross-talk with estrogen receptors, overexpression of Mucin 1 (MUC1) protein, insulin-like growth factor I receptor, etc., are key pathways involved in TR. In this review, we have provided a molecular view of TR and the possible remedies for overcoming TR using BC stem cell (BCSC)-based therapy, PI3K pathway inhibitors, MUC1-based treatment, etc. We have also analysed the patents and clinical trials from the pre-TR and post-TR era to rationalise the possible steps to overcome TR. Our analysis implies that Trastuzumab monotherapy no longer applies to HER2+ BC treatment. Further, combination therapy using other antibodies like pertuzumab and protein kinase inhibitors and targeting pathways like the ubiquitin proteasome pathway will be the future option for BC Treatment. Overall, this review provides a detailed summary of the molecular mechanisms involving TR and its potential ways of evasion, based on updated information from published research articles, clinical trial outcomes, and patent data.  \nKeywords: trastuzumab resistance; HER2 receptor; PI3K/AKT/mTOR pathway; Mucin1; combination therapy; patents & clinical trials  \n1. Introduction  \nIn 2020, the International Agency for Research on Cancer (IARC), a specialised cancer agency of the World Health Organisation (WHO), released a report that showed that breast cancer (BC) has overtaken lung cancer as the most prevalent cancer throughout the  \nglobe [1] . BC is also the leading cause of cancer-related deaths in women worldwide [2] . The observed over-expression of HER2 in approximately 20–30% of BC patients has encouraged researchers for years to find a drug/antibody to target HER2 so that the drug can stop HER2-mediated BC. In 1984, gene ‘neu’ [3] was isolated from rat neuro/glioblastoma encoding a protein with 185 KDa, similar to a gene located at the human q21 region of chromosome 17 [4] . Due to the significant similarities of the ‘neu’ gene with the protein se","cbCaif6oO2WLLluE","https://ap.wps.com/l/cbCaif6oO2WLLluE","pdf",3693316,32,"English","# Abstract\n# Keywords\n# 1. Introduction","[{\"question\":\"为什么曲妥珠单抗在乳腺癌治疗中会出现耐药？\",\"answer\":\"文中指出，耐药与PI3K通路相关的改变、与雌激素受体的信号交叉、以及MUC1等分子的异常表达有关，从而削弱了曲妥珠单抗阻断HER2介导信号的效果。\"},{\"question\":\"这篇综述主要从哪些方面梳理曲妥珠单抗耐药？\",\"answer\":\"综述从分子机制视角总结耐药，并讨论潜在应对策略，同时分析了耐药发生前后（pre-TR与post-TR）时期的临床试验与专利数据。\"},{\"question\":\"作者的总体结论是什么？治疗上未来更倾向哪类方案？\",\"answer\":\"文章认为曲妥珠单抗单药在HER2阳性乳腺癌治疗中不再适用；更有前景的是联合治疗，例如与帕妥珠单抗等抗体联合，以及联合蛋白激酶抑制剂并靶向如泛素-蛋白酶体通路等机制。\"}]","Trastuzumab Resistance, a Potential Roadblock for Most Successful Therapy of Breast Cancer - An Updated Review of Underlying Mechanisms, Clinical Trials and Patents to Evade the Resistance | PDF",1790127858,81]