A Three-subtype Molecular model of Cervical Cancer - Multiple PI3K Pathway inhibitors suppress growth and cooperate with HPV-directed immunotherapy

Sep 23, 2026

Uploaded by Eliana

Cervical cancer is driven by human papillomavirus (HPV) infections, yet lacks molecularly defined subtypes and has limited targeted options. 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.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages33

Reading Time1 h 23 min

AccessFree to download

Abstract

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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 The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. 1 A Three-subtype Molecular model of Cervical Cancer: Multiple PI3K 2 Pathway inhibitors suppress growth and cooperate with HPV-directed 3 immunotherapy 4 5 Hong Lou 1, David Langan2, Nick Syracuse3, Elizabeth A. Murphy4, Sojung Kim2, Emma 6 Robinson 1, Nicole M. Rossi3, Yi Xie3, Sonam Tulsyan3, Tawnjerae Joe3, Isabel Rodriguez3, Nina 7 Rao3, Matthew R. Oberley4, Mathias Oelke2, Michael Dean3* 8 9 1Cancer Genetics Research Laboratory, Division of Cancer Epidemiology and Genetics, 10 Frederick National Laboratory for Cancer Research, Gaithersburg, MD USA 11 2NexImmune, Gaithersburg, MD USA 12 3Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, 13 National Cancer Institute, Gaithersburg, MD USA 14 4Caris Life Sciences, Phoenix, AZ, USA 15 16 *Correspondence to: Michael Dean, Ph.D., Laboratory of Translational 17 Genomics, National Cancer Institute, Gaithersburg, MD 20877 USA. 18 Tel: 240-760-6484, 19 FAX: 301-402-3134 (email: [deanm@mail.nih.gov](deanm@mail.nih.gov)) 20 21 Running title: Alpelisib, Inavolisib, Capivasertib, and activated T cells to treat PIK3CA-mutated 22 cervical cancer 23 Key words: Cervical Cancer, Immunotherapy, Immune Checkpoint Inhibitor, Major 24 histocompatibility complex-MHC, Virology, real-world data, clinical outcomes 25 1 NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 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. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. 26 27 Graphical Abstract 28 29 30 31 32 33 Abstract 34 Objective: Cervical cancer is caused by human papillomavirus (HPV) infections; however, there 35 are no molecularly defined subtypes, and few approved targeted therapies. We defined molecular 36 subtypes and tested targeted agents. 37 Methods: Public datasets were analyzed; cell lines were treated with drugs; and donor T cells 38 and their proliferation were measured. 39 Results: We define three molecular subtypes: I, Wild type for PIK3CA/no YAP1 amplification; 40 II, PIK3CA mutation/no YAP1 amplification; III, PIK3CA WT/YAP1 amplification. Patients 41 with YAP1-amplified cervical cancer have poorer survival. The PI3K-specific inhibitors 42 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 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. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. 44 inhibitor, Capivasertib (AZD5363), suppressed some but not all tested PIK3CA-mutated cell 45 lines and one PIK3CA-wt cell line (SiHa) . Alpelisib inhibits the exp

FAQs

What molecular subtypes are proposed for cervical cancer, and what markers define them?

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).

Which PI3K inhibitors showed selective growth suppression in cervical cancer cell lines?

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).

How do PI3K inhibitors interact with HPV-directed T cell immunotherapy?

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.

Sep 23, 2026

Uploaded by Eliana