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

TL;DR

This study shows that targeting p110α/AKT and N-cadherin can improve treatment outcomes in ovarian cancer with PIK3CA abnormalities.

Contribution

The study identifies a novel therapeutic vulnerability in PIK3CA-aberrated ovarian cancer cells through co-targeting p110α/AKT and N-cadherin.

Findings

PIK3CA amplification and E545K mutation both activate AKT signaling, promoting cell migration.

AKT signaling increases cytoplasmic YAP levels and N-cadherin expression, enhancing migration.

Combined inhibition of p110α/AKT and N-cadherin reduces migration and metastasis in ovarian cancer.

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.

PIK3CA amplification and PIK3CA mutation enhance ovarian tumorigenicity through an activation of AKT, which phosphorylates YAP at Ser127. This Ser127 phosphorylation leads to the retention of YAP in the cytoplasm and triggers RAC1 activity, promoting cell migration. Additionally, AKT activation increases expression of N‐cadherin, which further enhances cell migration. This p110α/AKT/N‐cadherin signaling axis represents a potential therapeutic vulnerability.

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