Related Experiment Video

Updated: Feb 14, 2026

De Novo Generation of Somatic Stem Cells by YAP/TAZ
13:05

De Novo Generation of Somatic Stem Cells by YAP/TAZ

Published on: May 7, 2018

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

Keith C Garcia1,2, Ali A Khan1,2,3, Krishnendu Ghosh1

  • 1Department of Pathology.

JCI Insight
|February 12, 2026
PubMed

Insights

Phosphoinositide 3-kinase (PI3K) signaling drives sarcoma growth via TAZ/YAP. Targeting PI3K, TAZ/YAP-TEAD, and mTORC1 with combination therapy shows synergistic effects in preclinical sarcoma models.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling Pathways

Background:

  • Sarcomas are diverse cancers with limited targeted therapies.
  • Phosphoinositide 3-kinase (PI3K) signaling is frequently activated in sarcomas, often due to PTEN loss.
  • A downstream oncogenic transcription factor for the PI3K pathway was previously unidentified.

Purpose of the Study:

  • To identify downstream effectors of PI3K signaling in sarcoma.
  • To investigate the role of TAZ and YAP transcriptional co-activators in PI3K-driven sarcomas.
  • To explore combination therapies targeting PI3K, TAZ/YAP, and mTORC1 pathways.

Main Methods:

  • Utilized a PI3K-driven sarcoma mouse model.
  • Investigated the PI3K-TAZ/YAP signaling axis.
  • Evaluated combination therapy with a TEAD inhibitor (IK-930) and an mTORC1 inhibitor (everolimus) in vitro and in vivo.

Main Results:

  • TAZ and YAP are PI3K-regulated transcriptional co-activators driving sarcoma growth.
  • The PI3K-TAZ/YAP axis operates parallel to the PI3K-Akt-mTORC1 axis.
  • Combination therapy targeting TEAD and mTORC1 demonstrated synergistic reduction in sarcoma cell proliferation and growth in vivo.

Conclusions:

  • The PI3K-TAZ/YAP axis represents a novel therapeutic vulnerability in PI3K-activated sarcomas.
  • Combined inhibition of TAZ/YAP-TEAD and mTORC1 offers a promising synergistic therapeutic strategy.
  • An integrated approach targeting both PI3K and Hippo signaling pathways is crucial for treating PI3K-activated sarcomas.
Keywords:
CancerCell biologyOncologySignal transduction

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