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

[OBJECTIVE] Cervical 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.

[METHODS] Public datasets were analyzed; cell lines were treated with drugs; and donor T cells and their proliferation were measured.

[RESULTS] We define three molecular subtypes: I, Wild type for /no amplification; II, mutation/no amplification; III, WT/ amplification. Patients with -amplified cervical cancer have poorer survival. The PI3K-specific inhibitors Alpelisib (BYL-719) and Inavolisib (GDC0077) inhibit the proliferation of multiple -mutated cervical cancer cell lines, but not a wild-type (WT) line. The pan-AKT inhibitor, Capivasertib (AZD5363), suppressed some but not all tested -mutated cell lines and one -wt cell line (SiHa). Alpelisib inhibits the expression of the HPV16 E7 oncoprotein, /PD-L1, , and genes, only in PI3K-mutated cell lines. Treatment of an HPV16-positive, HLA-A2, 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.

[CONCLUSIONS] Our study revealed molecular inhibitors targeting mutant 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.