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

作者：Keith Garcia, Ali Khan, Krishnendu Ghosh, Sumit Sinha, Nicholas Scalora, Gillian DeWane, Colleen Fullenkamp, Nicole Merritt, Yuliia Drebot, Samuel Yu, Mariah Leidinger, Michael D. Henry, Patrick Breheny, Michael S. Chimenti, Munir R. Tanas · 发表于：JCI Insight · 年份：2026 · DOI：10.1172/jci.insight.191600 · 研究领域：Hippo pathway signaling and YAP/TAZ、Cellular Mechanics and Interactions、Developmental Biology and Gene Regulation

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.