PI3K regulates TAZ/YAP and mTORC1 and can synergistically be targeted in sarcomas
Sarcomas encompass heterogenous, difficult to treat cancers, lacking common therapeutic targets. Phosphatidylinositol-3 kinase (PI3K) signaling is activated in sarcomas to a greater degree than previously appreciated due to phosphatase and tensin homolog (PTEN) loss, and could represent such a target. Targeting PI3K signaling has largely focused on targeting mTORC1, considered the main effector of PI3K signaling, but this has not translated to success in the clinic, suggesting that there may be other effectors downstream of PI3K. One gap in our understanding of the PI3K signaling pathway has been the absence of a known oncogenic transcription factor. Herein we implicate TAZ and YAP as additional transcriptional effectors downstream of PI3K signaling regulated by a LATS1/2 dependent mechanism. Using in vitro and in vivo approaches, we show that TAZ and YAP are central oncoproteins in PI3K driven oncogenesis along with mTORC1, providing a rationale for combination therapy. Leveraging these findings, we describe a therapeutic approach that builds upon pre-existing therapeutic strategies utilizing mTORC1 inhibitors and combines them with new TEAD inhibitors that target YAP and TAZ. Combination therapy using everolimus and IK-930, an inhibitor targeting autopalmitoylation of the TEADs, synergistically diminished proliferation and anchorage dependent growth of PI3K activated sarcoma cell lines at low, physiologically achievable doses. In vivo, this combination therapy showed a synergistic effect, contrasting with the lack of effect of the individual single agent therapies, suggesting that an integrated view of PI3K and Hippo signaling can be leveraged therapeutically in PI3K activated sarcomas. Overall design: RNA was isolated from the tumors of genetically engineered mouse. Where, "Skel" is the control group and "PTEN", "YAP", "TAZ", "Quad" represent the experimental group. Each sample group had 5 replicates. RNA-seq was done to evaluate and study the differentially expressed genes in each group. PTEN: Trp53fl/fl Ptenfl/fl YAP: Trp53fl/fl Ptenfl/flYapfl/fl TAZ: Trp53fl/flPtenfl/flTazfl/fl QUAD: Trp53fl/flPtenfl/flYapfl/flTazfl/fl SKEL: skeletal muscle control