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

Keith C. Garcia; Ali A. Khan; Krishnendu Ghosh; Souradip 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

doi:10.1101/2025.01.21.634138

Back

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

Preprint

Open access

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

Keith C. Garcia, Ali A. Khan, Krishnendu Ghosh, Souradip Sinha, Nicholas Scalora, Gillian DeWane, Colleen Fullenkamp, Nicole Merritt, Yuliia Drebot, Samuel Yu, …

bioRxiv

Cold Spring Harbor Laboratory, 1.1

01/22/2025

DOI: 10.1101/2025.01.21.634138

PMCID: PMC11785051

PMID: 39896636

Files and links (1)

url

https://doi.org/10.1101/2025.01.21.634138View

Preprint (Author's original)This preprint has not been evaluated by subject experts through peer review. Preprints may undergo extensive changes and/or become peer-reviewed journal articles. Open Access

Abstract

Sarcomas are a heterogeneous group of cancers with few shared therapeutic targets. PI3K signaling is activated in various subsets of sarcomas, representing a shared oncogenic signaling pathway. Oncogenic PI3K signaling has been challenging to target therapeutically. An integrated view of PI3K and Hippo pathway signaling is examined to determine if this could be leveraged therapeutically. A tissue microarray containing sarcomas of various histological types was evaluated for PTEN loss and correlated with levels of activated TAZ and YAP. PI3K and Hippo pathways were dissected in sarcoma cell lines. The role of TAZ and YAP were evaluated in a PI3K-driven mouse model. The efficacy of mTORC1 inhibition and TEAD inhibition were evaluated in sarcoma cell lines and in vivo. PI3K signaling is frequently activated in sarcomas due to PTEN loss (in 30-60%), representing a common therapeutic target. TAZ and YAP are transcriptional co-activators regulated by PI3K and drive a transcriptome necessary for tumor growth in a PI3K-driven sarcoma mouse model. 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, reducing tumor proliferation and size. TAZ and YAP are transcriptional co-activators downstream of PI3K signaling, a pathway that has lacked a well-defined oncogenic transcription factor. This PI3K-TAZ/YAP axis exists in parallel to the known PI3K-Akt-mTORC1 axis allowing for synergistic combination therapy targeting the TAZ/YAP-TEAD interaction and mTORC1 in sarcomas.

Cancer Biology

Details

Title: Subtitle: PI3K regulates TAZ/YAP and mTORC1 axes that can be synergistically targeted
Creators: Keith C. Garcia - University of Iowa
Ali A. Khan - University of Iowa
Krishnendu Ghosh - University of Iowa
Souradip Sinha - University of Iowa
Nicholas Scalora - University of Iowa
Gillian DeWane - University of Iowa
Colleen Fullenkamp - University of Iowa
Nicole Merritt - University of Iowa
Yuliia Drebot - University of Iowa
Samuel Yu - University of Iowa
Mariah Leidinger - University of Iowa
Michael D. Henry - University of Iowa
Patrick Breheny - University of Iowa
Michael S. Chimenti - University of Iowa
Munir R. Tanas - University of Iowa
Resource Type: Preprint
Publication Details: bioRxiv
Edition: 1.1
DOI: 10.1101/2025.01.21.634138
PMID: 39896636
PMCID: PMC11785051
NLM abbreviation: bioRxiv
ISSN: 2692-8205
eISSN: 2692-8205
Publisher: Cold Spring Harbor Laboratory
Number of pages: 433
Language: English
Date posted: 01/22/2025
Academic Unit: Molecular Physiology and Biophysics; The University of Iowa Institute for Vision Research; Pathology; Biostatistics; Radiation Oncology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984786281002771

Metrics

14 Record Views