[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-328221-105":59,"doc-detail-328221-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","resistance-to-targeted-inhibitors-of-the-pi3kaktmtor-pathway-in-advanced-oestrogen-receptor-positive-breast-cancer","Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer","","The PI3K/AKT/mTOR signalling pathway is a highly activated driver in breast cancer and supports key physiological functions, making it a focal point for precision oncology. Despite development of multiple inhibitors targeting PI3K, AKT, and mTOR, only three agents are approved for advanced ER-positive, HER2-negative disease. Clinical use is constrained by resistance, which can be intrinsic or acquired, and by toxicity. The review synthesizes resistance mechanisms, current management approaches, and ongoing trials, emphasizing a need for further study of AKT1 inhibitor resistance.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/resistance-to-targeted-inhibitors-of-the-pi3kaktmtor-pathway-in-advanced-oestrogen-receptor-positive-breast-cancer/328221/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/resistance-to-targeted-inhibitors-of-the-pi3kaktmtor-pathway-in-advanced-oestrogen-receptor-positive-breast-cancer/328221.png","ImageObject",300,407,{"name":92,"@type":93},"Maeve","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-22","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What does the review cover about PI3K/AKT/mTOR pathway inhibitors in advanced ER-positive breast cancer?","Question",{"text":112,"@type":113},"It summarizes the PI3K/AKT/mTOR pathway, reviews mechanisms of resistance to inhibitors targeting the pathway, and discusses future strategies to overcome resistance in early lines of treatment.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which PI3K/AKT/mTOR-targeted inhibitors are approved for advanced ER-positive, HER2-negative breast cancer mentioned in the text?",{"text":117,"@type":113},"The text states that everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor) are the three approved inhibitors in this setting.",{"name":119,"@type":110,"acceptedAnswer":120},"How is drug resistance classified in this article?",{"text":121,"@type":113},"Resistance is categorized as intrinsic or acquired: intrinsic resistance exists prior to a specific treatment, while acquired resistance is induced by therapy.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},328221,1790653288,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},5909877438554,"https://ap-avatar.wpscdn.com/avatar/5600025385ad2bf12a7?_k=1778553567797529272","cancers   \nReview  \nResistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer  \nIseult M. Browne  and Alicia F. C. Okines *  \nCitation: Browne, I.M.; Okines, A.F.C. Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-ReceptorPositive Breast Cancer. Cancers 2024, 16, 2259. [https://doi.org/10.3390/](https://doi.org/10.3390/)  \ncancers16122259  \nAcademic Editor: Yang Yuqi  \nReceived: 24 May 2024  \nRevised: 11 June 2024  \nAccepted: 13 June 2024  \nPublished: 18 June 2024  \nCopyright: © 2024 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 ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \nBreast Unit, The Royal Marsden NHS Foundation Trust, London SW3 6JJ, UK; [iseult.browne@icr.ac.uk](iseult.browne@icr.ac.uk)  \n* Correspondence: [alicia.okines@rmh.nhs.uk](alicia.okines@rmh.nhs.uk); Tel.: +44-(0)-207-808-2748; Fax: +44-(0)-207-808-2563  \nSimple Summary: The outcomes for patients with advanced oestrogen-receptor-positive (ER-positive) breast cancer have improved significantly over the last decade. Whereas treatment of endocrineresistant disease was previously limited to conventional chemotherapy, we are now seeing increasing approvals for targeted agents suitable for combination with hormone therapies to potentially reverse the endocrine resistance for these patients in the early lines of treatment. The phosphoinositide-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is frequently dysregulated in human cancers, and though many drugs targeting this pathway have been developed, a vast number of these compounds have failed in clinical trials, with both toxicity and resistance being major problems. In this article, we summarise the PI3K/AKT/mTOR pathway, review the mechanisms of resistance to agents that target this pathway, and discuss future potential strategies to overcome this resistance.  \nAbstract: The PI3K/AKT/mTOR signalling pathway is one of the most frequently activated pathways in breast cancer and also plays a central role in the regulation of several physiologic functions. There are major efforts ongoing to exploit precision medicine by developing inhibitors that target the three kinases (PI3K, AKT, and mTOR) . Although multiple compounds have been developed, at present, there are just three inhibitors approved to target this pathway in patients with advanced ER-positive, HER2-negative breast cancer: everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor) . Like most targeted cancer drugs, resistance poses a major problem in the clinical setting and is a factor that has frequently limited the overall efficacy of these agents. Drug resistance can be categorised into intrinsic or acquired resistance depending on the timeframe it has developed within. Whereas intrinsic resistance exists prior to a specific treatment, acquired resistance is induced by a therapy. The majority of patients with ER-positive, HER2-negative advanced breast cancer will likely be offered an inhibitor of the PI3K/AKT/mTOR pathway at some point in their cancer journey, with the options available depending on the approval criteria in place and the cancer's mutation status. Within this large cohort of patients, it is likely that most will develop resistance at some point, which makes this an area of interest and an unmet need at present. Herein, we review the common mechanisms of resistance to agents that target the PI3K/AKT/mTOR signalling pathway, elaborate on current management approaches, and discuss ongoing clinical trials attempting to mitigate this significant issue. We highlight the need for additional studies into AKT1 inhibitor resistance in particular.  \nKeywords: adva","cbCaicH05xK445i1","https://ap.wps.com/l/cbCaicH05xK445i1","pdf",1878198,18,"English","# Introduction\n# PI3K/AKT and mTOR Signalling Pathway\n## Role in normal cellular processes\n## Activation in breast cancer and targeting rationale\n## Key genetic alterations (PIK3CA, AKT1, PTEN)\n# Resistance to Targeted Inhibitors in Advanced ER-Positive Disease\n## Intrinsic vs acquired resistance\n## Current management approaches\n## Future strategies and clinical trials","[{\"question\":\"What does the review cover about PI3K/AKT/mTOR pathway inhibitors in advanced ER-positive breast cancer?\",\"answer\":\"It summarizes the PI3K/AKT/mTOR pathway, reviews mechanisms of resistance to inhibitors targeting the pathway, and discusses future strategies to overcome resistance in early lines of treatment.\"},{\"question\":\"Which PI3K/AKT/mTOR-targeted inhibitors are approved for advanced ER-positive, HER2-negative breast cancer mentioned in the text?\",\"answer\":\"The text states that everolimus (mTOR inhibitor), alpelisib (PIK3CA inhibitor), and capivasertib (AKT inhibitor) are the three approved inhibitors in this setting.\"},{\"question\":\"How is drug resistance classified in this article?\",\"answer\":\"Resistance is categorized as intrinsic or acquired: intrinsic resistance exists prior to a specific treatment, while acquired resistance is induced by therapy.\"}]","Resistance to Targeted Inhibitors of the PI3K/AKT/mTOR Pathway in Advanced Oestrogen-Receptor-Positive Breast Cancer | PDF",1789978915,45]