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 Y. Yu, Mariah Leidinger, Michael D. Henry, Patrick J. Breheny, Michael S. Chimenti, Munir R. Tanas
Keith C. Garcia, Ali A. Khan, Krishnendu Ghosh, Souradip Sinha, Nicholas Scalora, Gillian DeWane, Colleen Fullenkamp, Nicole Merritt, Yuliia Drebot, Samuel Y. Yu, Mariah Leidinger, Michael D. Henry, Patrick J. Breheny, Michael S. Chimenti, Munir R. Tanas
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Research Article Cell biology Oncology

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

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.

Authors

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

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Figure 4

TAZ and YAP are critical oncoproteins in a PI3K-activated mouse model of sarcoma.

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TAZ and YAP are critical oncoproteins in a PI3K-activated mouse model of...
(A) Western blot analysis of 4 representative tumors (T1, T2, T3, and T4) from Trp53fl/flPtenfl/fl mice. (B) H&E section from a Trp53fl/flPtenfl/fl primary tumor. IHC for TAZ and YAP. (C) Schematic for mouse experiment. (D) Survival curves for each mouse cohort. (E) Principal component analysis of RNA expression for 5 representative samples from murine skeletal muscle and 2P, 2PW, 2PY, and 2PWY tumors. (F) Number of differentially expressed genes in 2P, 2PW, and 2PY tumors normalized to murine skeletal muscle. (G) Number of differentially expressed genes in 2PW, 2PY, and 2PWY tumors normalized to 2P tumors. (H) List of top biological processes and their respective differentially expressed genes (DEGs) for 2PW, 2PY, and 2PWY tumors; although Wnt10a is differentially expressed in 2PW mice, Wnt signaling as a biological process, overall, is not enriched. Statistical analysis for Kaplan-Meier survival analysis was performed with the log-rank (Mantel-Cox) test. The above experiment with 2P, 2PW, 2PY, and 2PWY mice was performed twice. To assess enrichment on RNA-Seq datasets, hypergeometric analyses and Matthews correlation coefficient calculations were carried out.