Abstract 2553: Elucidation of the downstream signaling of PIK3CA genomic alterations in serous ovarian cancer

Abstract

Abstract Genomic aberrations of PIK3CA, which encodes the catalytic subunit p110α of the class IA phosphatidylinositol 3-kinase (PI3K), is frequently observed in cancers. In ovarian cancer of the serous subtype (the most common histotype of the disease), PIK3CA amplification is dominant over single nucleotide mutations in multiple patient cohorts, suggesting the possibility that PIK3CA amplification is an alternative to PIK3CA “hot spot” mutation for serous ovarian tumorigenesis. However, whether PIK3CA amplification and mutation exert the same functional consequences on serous ovarian tumorigenesis remains uncertain. This study aims to explore and compare the functional roles between the two types of PIK3CA gene aberrations on tumorigenicity, cellular signaling, and therapeutic responses in serous ovarian cancer. We confirmed that both PIK3CA amplification and E545K mutation could induce multiple tumorigenic phenotypes in CRISPR/Cas9-mediated E545K knock-in or wild-type PIK3CA overexpressing serous ovarian cancer cell lines. Signaling pathway analyses showed that E545K knock-in cells, but not PIK3CA-overexpressing cells, had the MAPK signaling pathway activated and were sensitive to MAPK pathway inhibition. An induction of AKT phosphorylation and PDK1 phosphorylation was observed in both E545K knock-in cells and wild-type PIK3CA-overexpressing cells. Accordingly, these cells displayed higher sensitivity towards p110α or AKT inhibitors. Intriguingly, in line with previous report which demonstrated YAP as AKT substrate, the activation of AKT associated with an increase in YAP S127 phosphorylation in the knock-in or PIK3CA-overexpressing cells. AKT inhibition suppressed YAP phosphorylation. Corroborating with the role of S127 in nuclear exclusion of YAP, YAP accumulated in the cytoplasm of these cells, leading to reduced transcriptional activity of YAP. While the functional significance of YAP cytoplasmic accumulation is yet to be investigated, our results reveal the common and distinct downstream pathways between PIK3CA amplification and mutation. These findings may be applicable to p110α-targeting therapies in serous ovarian cancer. Citation Format: Shibo Zhang, Hei Ip Hong, Victor CY Mak, Yuan Zhou, Panpan Wang, Lydia Wai Ting Cheung. Elucidation of the downstream signaling of PIK3CA genomic alterations in serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2553.