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Using public datasets and in vitro drug testing, the study identifies three PIK3CA/YAP1-based molecular subtypes (I, II, III) and finds worse survival for YAP1-amplified disease. PI3K inhibitors Alpelisib and Inavolisib suppress proliferation in PIK3CA-mutant cervical cell lines selectively, while Capivasertib shows partial inhibition. The work further shows HPV16 E7, CD274/PD-L1, YAP1, and EGFR modulation and HPV-antigen T cell cooperation to enhance cytotoxicity, especially after drug pretreatment.",{"@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/a-three-subtype-molecular-model-of-cervical-cancer-multiple-pi3k-pathway-inhibitors-suppress-growth-and-cooperate-with-hpv-directed-immunotherapy/356316/",{"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/a-three-subtype-molecular-model-of-cervical-cancer-multiple-pi3k-pathway-inhibitors-suppress-growth-and-cooperate-with-hpv-directed-immunotherapy/356316.png","ImageObject",300,407,{"name":92,"@type":93},"Eliana","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 molecular subtypes are proposed for cervical cancer, and what markers define them?","Question",{"text":113,"@type":114},"The study defines three molecular subtypes based on PIK3CA status and YAP1 amplification: subtype I (PIK3CA wild type with no YAP1 amplification), subtype II (PIK3CA mutation without YAP1 amplification), and subtype III (PIK3CA wild type with YAP1 amplification).","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"Which PI3K inhibitors showed selective growth suppression in cervical cancer cell lines?",{"text":118,"@type":114},"Alpelisib (BYL-719) and Inavolisib (GDC0077) inhibit proliferation in multiple PIK3CA-mutated cervical cancer cell lines but not in a PIK3CA wild-type line. Capivasertib (AZD5363) suppressed some, but not all, tested PIK3CA-mutated lines and also affected one PIK3CA-wt line (SiHa).",{"name":120,"@type":111,"acceptedAnswer":121},"How do PI3K inhibitors interact with HPV-directed T cell immunotherapy?",{"text":122,"@type":114},"In HPV16-positive settings, Alpelisib inhibits HPV16 E7 and alters CD274/PD-L1, YAP1, and EGFR gene expression only in PI3K-mutated cell lines. Combining BYL-719 with donor-derived T cells increases T cell cytotoxicity against CaSki cells, with the strongest effect observed after BYL-719 pretreatment followed by subsequent T cell treatment.","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},356316,1790232039,{"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":146},4398048949847,"https://ap-avatar.wpscdn.com/avatar/400002536579ef2da7f?_k=1778318612642679267","medRxiv preprint doi: [https://doi.org/10.64898/2026.01.21.26344562](https://doi.org/10.64898/2026.01.21.26344562); this version posted January 23, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  \nThis article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \n1 A Three-subtype Molecular model of Cervical Cancer: Multiple PI3K  \n2 Pathway inhibitors suppress growth and cooperate with HPV-directed  \n3 immunotherapy  \n4  \n5 Hong Lou 1, David Langan2, Nick Syracuse3, Elizabeth A. Murphy4, Sojung Kim2, Emma  \n6 Robinson 1, Nicole M. Rossi3, Yi Xie3, Sonam Tulsyan3, Tawnjerae Joe3, Isabel Rodriguez3, Nina  \n7 Rao3, Matthew R. Oberley4, Mathias Oelke2, Michael Dean3* 8  \n9 1Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics,  \n10 Frederick National Laboratory for Cancer Research, Gaithersburg, MD USA  \n11 2NexImmune, Gaithersburg, MD USA  \n12 3Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics,  \n13 National Cancer Institute, Gaithersburg, MD USA  \n14 4Caris Life Sciences, Phoenix, AZ, USA  \n15  \n16 *Correspondence to: Michael Dean, Ph.D., Laboratory of Translational  \n17 Genomics, National Cancer Institute, Gaithersburg, MD 20877 USA.  \n18 Tel: 240-760-6484,  \n19 FAX: 301-402-3134 (email: [deanm@mail.nih.gov](deanm@mail.nih.gov)) 20  \n21 Running title: Alpelisib, Inavolisib, Capivasertib, and activated T cells to treat PIK3CA-mutated  \n22 cervical cancer  \n23 Key words: Cervical Cancer, Immunotherapy, Immune Checkpoint Inhibitor, Major  \n24 histocompatibility complex-MHC, Virology, real-world data, clinical outcomes 25  \n1  \nNOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.  \nmedRxiv preprint doi: [https://doi.org/10.64898/2026.01.21.26344562](https://doi.org/10.64898/2026.01.21.26344562); this version posted January 23, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  \nThis article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \n26  \n27 Graphical Abstract 28  \n29  \n30  \n31  \n32   \n33 Abstract  \n34 Objective: Cervical cancer is caused by human papillomavirus (HPV) infections; however, there  \n35 are no molecularly defined subtypes, and few approved targeted therapies. We defined molecular  \n36 subtypes and tested targeted agents.  \n37 Methods: Public datasets were analyzed; cell lines were treated with drugs; and donor T cells  \n38 and their proliferation were measured.  \n39 Results: We define three molecular subtypes: I, Wild type for PIK3CA/no YAP1 amplification;  \n40 II, PIK3CA mutation/no YAP1 amplification; III, PIK3CA WT/YAP1 amplification. Patients  \n41 with YAP1-amplified cervical cancer have poorer survival. The PI3K-specific inhibitors  \n42 Alpelisib (BYL-719) and Inavolisib (GDC0077) inhibit the proliferation of multiple PIK3CA- 43 mutated cervical cancer cell lines, but not a PIK3CA wild-type (WT) line. The pan-AKT  \nmedRxiv preprint doi: [https://doi.org/10.64898/2026.01.21.26344562](https://doi.org/10.64898/2026.01.21.26344562); this version posted January 23, 2026. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.  \nThis article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available  \nfor use under a CC0 license.  \n44 inhibitor, Capivasertib (AZD5363), suppressed some but not all tested PIK3CA-mutated cell  \n45 lines and one PIK3CA-wt cell line (SiHa) . Alpelisib inhibits the exp","cbCaifFQ6MuRqMoF","https://ap.wps.com/l/cbCaifFQ6MuRqMoF","pdf",690258,33,"English","# Abstract\n## Objective\n## Methods\n## Results\n## Conclusions\n# Highlights\n# Introduction","[{\"question\":\"What molecular subtypes are proposed for cervical cancer, and what markers define them?\",\"answer\":\"The study defines three molecular subtypes based on PIK3CA status and YAP1 amplification: subtype I (PIK3CA wild type with no YAP1 amplification), subtype II (PIK3CA mutation without YAP1 amplification), and subtype III (PIK3CA wild type with YAP1 amplification).\"},{\"question\":\"Which PI3K inhibitors showed selective growth suppression in cervical cancer cell lines?\",\"answer\":\"Alpelisib (BYL-719) and Inavolisib (GDC0077) inhibit proliferation in multiple PIK3CA-mutated cervical cancer cell lines but not in a PIK3CA wild-type line. Capivasertib (AZD5363) suppressed some, but not all, tested PIK3CA-mutated lines and also affected one PIK3CA-wt line (SiHa).\"},{\"question\":\"How do PI3K inhibitors interact with HPV-directed T cell immunotherapy?\",\"answer\":\"In HPV16-positive settings, Alpelisib inhibits HPV16 E7 and alters CD274/PD-L1, YAP1, and EGFR gene expression only in PI3K-mutated cell lines. Combining BYL-719 with donor-derived T cells increases T cell cytotoxicity against CaSki cells, with the strongest effect observed after BYL-719 pretreatment followed by subsequent T cell treatment.\"}]","A Three-subtype Molecular model of Cervical Cancer - Multiple PI3K Pathway inhibitors suppress growth and cooperate with HPV-directed immunotherapy | PDF",1790124622,83]