Abstract 3747: Long-read whole genome sequencing identifies genes for targeted therapy to treat cervical cancer

Invasive cervical cancer (ICC) is the most common cause of death due to cancer for women living in poverty worldwide. However, there are no approved targeted therapies or schemes to divide cervical cancer for treatment. To address this, we have performed exome and long-read whole genome sequencing (WGS) of 450 ICC tumors from Guatemala. In addition, we performed 50-100X long-read WGS on 29 cervical cancer cell lines. This includes nearly all publicly available cell lines. We extended these findings using 807 ICC samples from cBioPortal (TCGA, AACR-Genie, MSKCC met). The two most commonly activated oncogenes in ICC are PIK3CA (mutated in 35% of tumors) and YAP1 (amplified in 10-14% of ICC). PIK3CA mutations and YAP1 amplifications are mutually exclusive and together define three subtypes. I-wild-type (WT) for both genes, II-PIK3CA-mutated, III-YAP1 amplified. Alpelisib is approved for PIK3CA-mutated breast cancer, and in the initial first-in-human trial, all five ICC patients responded. We treated three PIK3CA-mutated cervical cancer cell lines. Alpelisib causes a dramatic decrease in proliferation at the lowest dose (5 uM) but not in PIK3CA WT cell lines. Responsive cells displayed reduced expression of the HPV E7 oncoprotein and the checkpoint inhibitor CD274/PD-L1 protein. As PD-L1 inhibits cytotoxic T cells, we tested Alpelisib in combination with patient-activated T cells to HPV antigens and found the combined treatment showed optimum cell killing. We demonstrated that YAP1 amplification defines an aggressive subtype of ICC with a 14-year earlier age of onset and poorer survival, even in stage 1 ICC. YAP1 amplification is 3-fold more common in African American and twice as common in Asian ICC. WGS of cell lines and tumors demonstrates that 95% of YAP1 amplification occurs through breakage-fusion-bridge events that co-amplify the anti-apoptotic BIRC2/3 genes. Currently, there are no approved YAP1 inhibitors, but in cervical cells, YAP1 acts to upregulate epidermal growth factor (EGF) ligands and the EGF receptor (EGFR). We tested the EGFR inhibitor Lapatinib on YAP1-amplified CaSki cells and found a five-fold reduction in proliferation. Additional recurrent driver genes in ICC that may be targeted for therapy include MYC, PTEN, KRAS, FBXW7, and STK11. We conclude that oral PI3K inhibitors such as Alpelisib are a viable therapeutic option for up to 200,000 cervical patients annually and may enhance immunotherapies. Initial results suggest that EGFR pathway inhibitors may be beneficial in the most aggressive subtype of ICC. Our cell line panel can allow the testing of additional therapeutics to the YAP1 and other pathways to expand treatment further. Citation Format: Michael C. Dean, Sonam Tulsyan, Hong Lou, Emma Robinson, Ayse Keskus, Tanveer Ahmad, Isabel Rodriguez, Yi Xie, Jia Liu, Wen Luo, Herbert Higson, David Langan, Sojung Kim, Mathias Oelke, Mikhail Kolmogorov. Long-read whole genome sequencing identifies genes for targeted therapy to treat cervical cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3747.