# PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted

## TL;DR

This study identifies a new therapeutic target in sarcomas by showing that PI3K signaling regulates TAZ/YAP and mTORC1, which can be effectively inhibited together.

## Contribution

The study reveals a novel PI3K/TAZ/YAP axis in sarcomas and demonstrates the therapeutic potential of combining TEAD and mTORC1 inhibitors.

## Key findings

- PI3K signaling is frequently activated in sarcomas due to PTEN loss.
- TAZ and YAP are transcriptional coactivators regulated by PI3K and drive tumor growth.
- Combining TEAD and mTORC1 inhibitors synergistically reduces tumor growth in vitro and in vivo.

## Abstract

Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. We show that PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30%–60%), representing a common therapeutic target. The PI3K pathway has lacked a downstream oncogenic transcription factor. We show TAZ and YAP are transcriptional coactivators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. This PI3K/TAZ/YAP axis exists in parallel to the known PI3K/AKT/mTORC1 axis, providing a rationale for combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1. Combination therapy using IK-930 (TEAD inhibitor) and everolimus (mTORC1 inhibitor) synergistically diminished proliferation and anchorage-independent growth of PI3K-activated sarcoma cell lines at low, physiologically achievable doses. Furthermore, this combination therapy showed a synergistic effect in vivo, suggesting that an integrated view of PI3K and Hippo signaling can be leveraged therapeutically in PI3K-activated sarcomas.

PI3K signaling is active in sarcomas of different histological types. A PI3K-TAZ/YAP axis exists in addition to the PI3K-Akt-mTORC1 axis that can be synergistically targeted.