Related Experiment Video

Updated: May 29, 2025

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter
11:32

Identification of Transcription Factor Regulators using Medium-Throughput Screening of Arrayed Libraries and a Dual-Luciferase-Based Reporter

Published on: March 27, 2020

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

Keith C Garcia, Ali A Khan, Krishnendu Ghosh

    Biorxiv : the Preprint Server for Biology
    |February 3, 2025
    PubMed
    Abstract

    Insights

    Targeting the PI3K-TAZ/YAP pathway with combination therapy, including TEAD and mTORC1 inhibitors, shows promise for treating PI3K-activated sarcomas. This approach synergistically reduces tumor growth and proliferation in preclinical models.

    Area of Science:

    • Oncology
    • Molecular Biology
    • Cancer Therapeutics

    Background:

    • Sarcomas are a diverse cancer group with limited targeted therapies.
    • Phosphoinositide 3-kinase (PI3K) signaling is frequently activated in sarcomas, often due to PTEN loss, presenting a potential therapeutic vulnerability.
    • Targeting PI3K signaling has been clinically challenging.

    Purpose of the Study:

    • To investigate the interplay between PI3K and Hippo pathway signaling in sarcomas.
    • To explore the therapeutic potential of targeting the PI3K-TAZ/YAP axis in sarcomas.

    Main Methods:

    • Evaluated PTEN loss and TAZ/YAP activation in sarcoma tissue microarrays.
    • Dissected PI3K and Hippo pathway signaling in sarcoma cell lines.
    • Assessed TAZ and YAP roles in a PI3K-driven mouse model.
    • Tested the efficacy of mTORC1 and TEAD inhibitors, alone and in combination, in vitro and in vivo.

    Main Results:

    • PI3K signaling, activated by PTEN loss in 30-60% of sarcomas, was linked to TAZ and YAP transcriptional co-activators.
    • TAZ and YAP drive tumor growth in PI3K-activated sarcomas.
    • Combination therapy with a TEAD inhibitor (IK-930) and an mTORC1 inhibitor (everolimus) demonstrated synergistic anti-proliferative effects in vitro and reduced tumor growth in vivo.

    Conclusions:

    • The PI3K-TAZ/YAP axis represents a critical oncogenic pathway in sarcomas, acting parallel to the PI3K-Akt-mTORC1 axis.
    • This axis provides a novel therapeutic target.
    • Combined inhibition of TAZ/YAP-TEAD interaction and mTORC1 offers a promising synergistic strategy for treating PI3K-activated sarcomas.

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