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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/jci.insight.191600

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

Keith C. Garcia,1 Ali A. Khan,1 Krishnendu Ghosh,1 Souradip Sinha,1 Nicholas Scalora,1 Gillian DeWane,1 Colleen Fullenkamp,1 Nicole Merritt,1 Yuliia Drebot,1 Samuel Y. Yu,1 Mariah Leidinger,1 Michael D. Henry,2 Patrick J. Breheny,3 Michael S. Chimenti,4 and Munir R. Tanas1

1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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1Department of Pathology, The University of Iowa, Iowa City, United States of America

2Department of Biostatistics, The University of Iowa, Iowa City, United States of America

3Biostatistics, The University of Iowa, Iowa City, United States of America

4Iowa Institute of Human Genetics, The University of Iowa, Iowa City, United States of America

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Published February 12, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.191600.
Copyright © 2026, Garcia et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published February 12, 2026 - Version history
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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 co-activators 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 dependent 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.

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graphical abstract
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