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This review summarizes resistance mechanisms—PI3K reactivation via PIK3CA mutations and PTEN loss, compensatory pathway activation, and feedback loop–driven signaling—then evaluates how recent combination clinical trials address these barriers and their current limitations.",{"@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/research-report/","Research & 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do PI3K pathway inhibitors show limited clinical activity in gynecological cancers despite common pathway alterations?","Question",{"text":63,"@type":64},"Limited activity is attributed to resistance mechanisms that reduce inhibitor effectiveness, including de novo refractoriness and acquired resistance after treatment begins.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What genetic and signaling changes can reactivate the PI3K pathway during PI3K inhibitor therapy?",{"text":68,"@type":64},"Reactivation can occur through genetic alterations such as PIK3CA mutations and PTEN loss, alongside compensatory signaling pathway activation and feedback loops.",{"name":70,"@type":61,"acceptedAnswer":71},"How does this review connect resistance mechanisms to combination therapy trials?",{"text":72,"@type":64},"The review links specific resistance drivers to combination therapy approaches, summarizing recent clinical trials that aim to overcome resistance and discussing their successes 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Inhibitors in Gynecological Cancers  \nKristen R. Ibanez , Tzu-Ting Huang *,† and Jung-Min Lee †  \nCitation: Ibanez, K.R.; Huang, T.-T.; Lee, J.-M. Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers. Cells 2024, 13, 1064. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)cells13121064  \nAcademic Editors: Jean Christopher Chamcheu, Claudia Bürger and Shile Huang  \nReceived: 29 May 2024  \nRevised: 16 June 2024  \nAccepted: 18 June 2024  \nPublished: 19 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/)) .  \nWomen’s Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of  \nHealth, Bethesda, MD 20892, USA; [kr892361@ucf.edu](kr892361@ucf.edu) (K.R.I.); [leej6@mail.nih.gov](leej6@mail.nih.gov) (J.-M.L.)  \n* Correspondence: [tzu-ting.huang@nih.gov](tzu-ting.huang@nih.gov); Tel.: +1-240-858-3279 † These authors contributed equally to this work.  \nAbstract: The PI3K signaling pathway plays an essential role in cancer cell proliferation and survival. PI3K pathway inhibitors are now FDA-approved as a single agent treatment or in combination for solid tumors such as renal cell carcinoma or breast cancer. However, despite the high prevalence of PI3K pathway alterations in gynecological cancers and promising preclinical activity in endometrial and ovarian cancer models, PI3K pathway inhibitors showed limited clinical activity in gynecological cancers. In this review, we provide an overview on resistance mechanisms against PI3K pathway inhibitors that limit their use in gynecological malignancies, including genetic alterations that reactivate the PI3K pathway such as PIK3CA mutations and PTEN loss, compensatory signaling pathway activation, and feedback loops causing the reactivation of the PI3K signaling pathway. We also discuss the successes and limitations of recent clinical trials aiming to address such resistance mechanisms through combination therapies.  \nKeywords: PI3K/AKT/mTOR inhibitors; resistance mechanisms; combination treatment; targeted therapy; gynecological cancer  \n1. Introduction  \nThe phosphoinositide 3-kinase (PI3K) pathway is essential for regulating cell metabolism, growth, and proliferation under normal physiological conditions. However, the aberrant activation of this pathway is a common oncogenic driver in various solid tumors [1]. Targeting the PI3K pathway has become a critical focus in cancer therapy, leading to the development and FDA approval of several inhibitors over the past two decades. Initially, mTOR inhibitors such as everolimus and temsirolimus were approved for treating renal cell carcinoma, followed by approvals for other solid tumors [2]. More recently, alpelisib and capivasertib, PI3Kα and AKT inhibitors, respectively, have been approved in combination with fulvestrant for hormone receptor-positive, HER2-negative metastatic breast cancer [3].  \nDespite the frequent dysregulation of the PI3K pathway in gynecological cancers such as endometrial cancer (EC) and ovarian carcinoma (OC), PI3K pathway inhibitors have yet to show sufficient clinical efficacy for approval in these settings [4] . Early clinical trials investigating PI3K pathway inhibitor monotherapies in EC and OC have demonstrated only modest activity, failing to replicate the promising results observed in preclinical studies [4] . This discrepancy is likely due to various resistance mechanisms that limit the effectiveness of PI3K pathway inhibitors in these tumors. The presence of de novo resistance mechanisms, where ","cbCaio9VmeXwwkGk","https://ap.wps.com/l/cbCaio9VmeXwwkGk","pdf",1996031,24,"English","# Introduction\n# Brief Overview of PI3K Pathway and the FDA-Approved PI3K Inhibitors\n# Resistance Mechanisms to PI3K Pathway Inhibitors in Gynecological Cancers\n# Combination Therapy Strategies to Overcome Resistance\n# Clinical Trials: Successes and Limitations","[{\"question\":\"Why do PI3K pathway inhibitors show limited clinical activity in gynecological cancers despite common pathway alterations?\",\"answer\":\"Limited activity is attributed to resistance mechanisms that reduce inhibitor effectiveness, including de novo refractoriness and acquired resistance after treatment begins.\"},{\"question\":\"What genetic and signaling changes can reactivate the PI3K pathway during PI3K inhibitor therapy?\",\"answer\":\"Reactivation can occur through genetic alterations such as PIK3CA mutations and PTEN loss, alongside compensatory signaling pathway activation and feedback loops.\"},{\"question\":\"How does this review connect resistance mechanisms to combination therapy trials?\",\"answer\":\"The review links specific resistance drivers to combination therapy approaches, summarizing recent clinical trials that aim to overcome resistance and discussing their successes and remaining limitations.\"}]","Combination Therapy Approach to Overcome the Resistance to PI3K Pathway Inhibitors in Gynecological Cancers | PDF",1790002638]