PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted.
basic_science · Level V
Where this comes from
- Record sourced from PubMed, PMID 41678521.
- Also identified by DOI 10.1172/jci.insight.191600 and PMC identifier 13043097.
- Licence recorded as CC BY.
- The licence permits redistribution, so the abstract is shown in full and the full text is available from the publisher.
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.
Medical subject headings
- Mechanistic Target of Rapamycin Complex 1
- Transcription Factors
- Phosphatidylinositol 3-Kinases
- Sarcoma
- Adaptor Proteins, Signal Transducing