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

ObjectiveCervical cancer is caused by human papillomavirus (HPV) infections; however, there are no molecularly defined subtypes, and few approved targeted therapies. We defined molecular subtypes and tested targeted agents. MethodsPublic datasets were analyzed; cell lines were treated with drugs; and donor T cells and their proliferation were measured. ResultsWe define three molecular subtypes: I, Wild type for PIK3CA/no YAP1 amplification; II, PIK3CA mutation/no YAP1 amplification; III, PIK3CA WT/YAP1 amplification. Patients with YAP1-amplified cervical cancer have poorer survival. The PI3K-specific inhibitors Alpelisib (BYL-719) and Inavolisib (GDC0077) inhibit the proliferation of multiple PIK3CA-mutated cervical cancer cell lines, but not a PIK3CA wild-type (WT) line. The pan-AKT inhibitor, Capivasertib (AZD5363), suppressed some but not all tested PIK3CA-mutated cell lines and one PIK3CA-wt cell line (SiHa). Alpelisib inhibits the expression of the HPV16 E7 oncoprotein, CD274/PD-L1, YAP1, and EGFR genes, only in PI3K-mutated cell lines. Treatment of an HPV16-positive, HLA-A2, PIK3CA mutant cell line (CaSki) with T cells (NexImmune), specific to HPV16 tumor antigens inhibited in a T cell: target cell ratio-dependent manner. BYL-719, in combination with donor T cells, enhances cytotoxicity against CaSki cells. Furthermore, pretreatment with BYL-719 and removing the drug, followed by treatment with donor T cells, had the maximum effect. ConclusionsOur study revealed molecular inhibitors targeting mutant PIK3CA cervical cancer. When combined with immune therapies, these agents may improve outcomes of advanced HPV16 cancers. Further research on targeted therapies will improve the prognosis of patients with cervical cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=156 SRC="FIGDIR/small/26344562v1_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@d56c22org.highwire.dtl.DTLVardef@1ae5edforg.highwire.dtl.DTLVardef@d697d9org.highwire.dtl.DTLVardef@8b6483_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIIdentified 3 molecular subtypes of CC based on PIK3CA and YAP1 amplification status C_LIO_LICervical cell lines with PIK3CA mutation are suppressed by targeted inhibitors C_LIO_LIPI3K inhibitors Alpelisib/Inavolisib selectively block PIK3CA-mutant cells C_LIO_LIPIK3CA mutation is associated with higher expression of the checkpoint CD274/PD-L1 C_LIO_LIPI3K inhibitors cooperate with donor-derived T cells to kill cervical cells C_LI