Vertical inhibition of p110α/AKT and N-cadherin enhances treatment efficacy in PIK3CA-aberrated ovarian cancer cells.

Abstract

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [PIK3CA, encoding PI3Kalpha (also known as p110α)] is one of the most commonly aberrated genes in human cancers. In serous ovarian cancer, PIK3CA amplification is highly frequent but PIK3CA point mutation is rare. However, whether PIK3CA amplification and PIK3CA driver mutations have the same functional impact in the disease is unclear. Here, we report that both PIK3CA amplification and E545K mutation are tumorigenic. While the protein kinase B (AKT) signaling axis was activated in both E545K knock-in cells and PIK3CA-overexpressing cells, the mitogen-activated protein kinase 3/1 (ERK1/2) pathway was induced selectively by E545K mutation but not PIK3CA amplification. Intriguingly, AKT signaling in these PIK3CA-aberrated cells increased transcriptional coactivator YAP1 (YAP) Ser127 phosphorylation and thereby cytoplasmic YAP levels, which in turn increased cell migration through Ras-related C3 botulinum toxin substrate 1 (RAC1) activation. In addition to the altered YAP signaling, AKT upregulated N-cadherin expression, which also contributed to cell migration. Pharmacological inhibition of N-cadherin reduced cell migratory potential. Importantly, co-targeting N-cadherin and p110α/AKT caused additive reduction in cell migration in vitro and metastases formation in vivo. Together, this study reveals the molecular pathways driven by the PIK3CA aberrations and the exploitable vulnerabilities in PIK3CA-aberrated serous ovarian cancer cells.