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A prior work identified a positive feedback loop among Ras, PI3K, the cytoskeleton, and FAK that enables Ras signaling excitability. Here, combined FAK and PI3K inhibition was tested in cervical and pancreatic cancer cells dependent on Ras/PI3K activity, showing synergistic suppression via increased apoptosis and reduced mitosis.",{"@graph":69,"@context":123},[70,84,106],{"@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/targeting-signaling-excitability-in-cervical-and-pancreatic-cancer-cells-through-combined-inhibition-of-fak-and-pi3k/372283/",{"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/targeting-signaling-excitability-in-cervical-and-pancreatic-cancer-cells-through-combined-inhibition-of-fak-and-pi3k/372283.png","ImageObject",300,407,{"name":92,"@type":93},"Ophelia","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What signaling mechanism is targeted in this study?","Question",{"text":113,"@type":114},"The study targets Ras/PI3K/ERK signaling excitability by using combined inhibition of FAK and PI3K.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What effect does combined FAK and PI3K inhibition have on cancer cell behavior?",{"text":118,"@type":114},"The combination synergistically suppresses growth of cervical and pancreatic cancer cell lines by increasing apoptosis and decreasing mitosis.",{"name":120,"@type":111,"acceptedAnswer":121},"Why can PI3K inhibition alone be insufficient?",{"text":122,"@type":114},"PI3K inhibitors alone only cause transient suppression of AKT and paradoxically increase FAK signaling in cancer cells, reducing effectiveness.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},372283,1790240440,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":36},7971461741311,"https://ap-avatar.wpscdn.com/avatar/74000253aff267980c6?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779345379180704826","Article  \nTargeting Signaling Excitability in Cervical and Pancreatic Cancer Cells Through Combined Inhibition of FAK and PI3K  \nChao-Cheng Chen 1,†, Suyang Wang 1, Jr-Ming Yang 1, * and Chuan-Hsiang Huang 1,2,3, *  \nAcademic Editor: Alicja Forma  \nReceived: 4 March 2025  \nRevised: 19 March 2025  \nAccepted: 24 March 2025  \nPublished: 26 March 2025  \nCitation: Chen, C.-C.; Wang, S.; Yang, J.-M.; Huang, C.-H. Targeting Signaling Excitability in Cervical and Pancreatic Cancer Cells Through Combined Inhibition ofFAK andPI3K. Int. J. Mol. Sci. 2025, 26, 3040. [https://](https://)[ ](https://)[doi.org/10.3390/ijms26073040](doi.org/10.3390/ijms26073040)  \n[Copyright:](Copyright:) © 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 ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA; [jimmy10421@gmail.com](jimmy10421@gmail.com) (C.-C.C.)  \n2 Department of Cell Biology, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA  \n3 Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA  \n* [Correspondence: jyang38@jhmi.edu](Correspondence: jyang38@jhmi.edu) (J.-M.Y.); [chuang29@jhmi.edu](chuang29@jhmi.edu) (C.-H.H.)† Present address: BC Cancer Research Institute Vancouver, BC V5Z 1L3, Canada.  \nAbstract: The Ras/PI3K/ERK signaling network is frequently mutated and overactivated in various human cancers. Focal adhesion kinase (FAK) is commonly overexpressed in several cancer types and has been implicated in treatment resistance mechanisms. A positive feedback loop between Ras, PI3K, the cytoskeleton, and FAK was previously shown to drive Ras signaling excitability. In this study, we investigated the effectiveness of targeting Ras signaling excitability by concurrently inhibiting FAK and PI3K in cervical and pancreatic cancer cells, which depend on activation Ras/PI3K signaling. We found that the combination of FAK and PI3K inhibitors synergistically suppressed the growth of cervical and pancreatic cancer cell lines through increased apoptosis and decreased mitosis. PI3K inhibitors alone caused only a transient suppression of downstream AKT activity and paradoxically increased FAK signaling in cancer cells. The addition of an FAK inhibitor effectively counteracted this PI3K-inhibitor-induced FAK activation. Furthermore, PI3K inhibitors were found to activate multiple receptor tyrosine kinases (RTKs), including insulin receptor, IGF-1R, EGFR, HER2, HER3, AXL, and EphA2 . Taken together, our results suggest that FAK inhibition is necessary to counteract the compensatory RTK activation induced by PI3K inhibitors, thereby achieving more effective suppression of cancer cell growth. These findings highlight the therapeutic potential of combined FAK and PI3K inhibition in cancer treatment.  \nKeywords: RTK/Ras/PI3K/ERK signaling network; excitability; drug combination; targeted therapy; synergy  \n1. Introduction  \nThe signaling network involving Ras GTPases and their downstream effectors, including the phosphoinositide 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways, regulates diverse cellular processes such as proliferation, differentiation, apoptosis, metabolism, protein synthesis, and motility [1] . Aberrant activation of this network, through mutations or overexpression, is frequently observed in human cancers [2] . For instance, 10–36% of cervical cancers harbor activating mutations in PIK3CA, which encodes the catalytic subunit of PI3Kα [3–6], while KRAS mutations are present in approximately 8% of non-squamous cell carcinomas of the cervix [7] . The MAPK/ERK pathway has also been implicated in cervical cancer pathog","cbCailbbLr6VUhnP","https://ap.wps.com/l/cbCailbbLr6VUhnP","pdf",9582363,16,"English","# Abstract\n# Introduction","[{\"question\":\"What signaling mechanism is targeted in this study?\",\"answer\":\"The study targets Ras/PI3K/ERK signaling excitability by using combined inhibition of FAK and PI3K.\"},{\"question\":\"What effect does combined FAK and PI3K inhibition have on cancer cell behavior?\",\"answer\":\"The combination synergistically suppresses growth of cervical and pancreatic cancer cell lines by increasing apoptosis and decreasing mitosis.\"},{\"question\":\"Why can PI3K inhibition alone be insufficient?\",\"answer\":\"PI3K inhibitors alone only cause transient suppression of AKT and paradoxically increase FAK signaling in cancer cells, reducing effectiveness.\"}]","Targeting Signaling Excitability in Cervical and Pancreatic Cancer Cells Through Combined Inhibition of FAK and PI3K | PDF",1790194156]