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 1

PI3K is widely activated in sarcomas.

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PI3K is widely activated in sarcomas. (A) The Cancer Genome Atlas (TCGA)...
(A) The Cancer Genome Atlas (TCGA) data (cBioPortal online) for PI3K signaling alterations in sarcomas (n = 253) demonstrating the incidence of mutations in the PI3K signaling pathway. (B) TCGA data demonstrating the frequency of genetic alterations of PTEN in sarcomas (n = 253). (C) H&E and IHC performed for PTEN, TAZ, and YAP on adult-type rhabdomyosarcoma from tissue microarray. Inset for PTEN shows vascular positive control. Insets for activated (nuclear) TAZ and YAP. (D) H-scores from clinical tissue microarray panel of various sarcoma histological subtypes. See supplemental materials for abbreviations used. Histology, H&E staining, and IHC for PTEN, TAZ, and YAP in a sample of alveolar rhabdomyosarcoma (ARMS). (E) Number of sarcomas exhibiting low PTEN/high TAZ expression relative to high PTEN/high TAZ expression (left) and composition of sarcomas exhibiting low PTEN/high TAZ profile according to histological type (right). (F) Number of sarcomas exhibiting low PTEN/high YAP expression relative to high PTEN/high YAP expression (left) and composition of sarcomas exhibiting low PTEN/high YAP profile according to histological type (right). Two-tailed P values for IHC counts were evaluated using the χ2 test with 1 degree of freedom. **P < 0.01, ***P < 0.001.