New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

Zhao, Yang; Sheldon, Marisela; Sun, Yutong; Ma, Li

doi:10.3390/cancers15235497

Cited by 9 publications

(3 citation statements)

References 267 publications

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“…Because YAP lacks a DNA binding domain, binding to one of the TEAD family proteins within the nucleus is required to promote transcription of Hippo target genes [ 10 ]. YAP and TEAD binding occurs via a large, flat surface which is difficult to target with small molecules as there are no obvious binding pockets [ 18 ]. However, recent efforts have been successful by targeting TEAD palmitoylation binding sites, which are essential for YAP-TEAD binding [ 19 ].…”

Section: Resultsmentioning

confidence: 99%

Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

Benton,

Yee Chow,

Karchugina

et al. 2024

PLoS ONE

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Neurofibromatosis type 2 is a genetic disorder that results in the formation and progressive growth of schwannomas, ependymomas, and/or meningiomas. The NF2 gene encodes the Merlin protein, which links cell cortical elements to the actin cytoskeleton and regulates a number of key enzymes including Group I p21-activated kinases (PAKs), the Hippo-pathway kinase LATS, and mTORC. While PAK1 and PAK2 directly bind Merlin and transmit proliferation and survival signals when Merlin is mutated or absent, inhibition of Group 1 PAKs alone has not proven sufficient to completely stop the growth of NF2-deficient meningiomas or schwannomas in vivo, suggesting the need for a second pathway inhibitor. As the Hippo pathway is also activated in NF2-deficient cells, several inhibitors of the Hippo pathway have recently been developed in the form of YAP-TEAD binding inhibitors. These inhibitors prevent activation of pro-proliferation and anti-apoptotic Hippo pathway effectors. In this study, we show that PAK inhibition slows cell proliferation while TEAD inhibition promotes apoptotic cell death. Finally, we demonstrate the efficacy of PAK and TEAD inhibitor combinations in several NF2-deficient Schwannoma cell lines.

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Section: Resultsmentioning

confidence: 99%

Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

Benton,

Yee Chow,

Karchugina

et al. 2024

PLoS ONE

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“…YAP/TAZ enters the nucleus in an active state to interact with TEAD leading to enhanced transcription ( Figure 1 ). YAP/TAZ is negatively regulated by the Hippo signaling pathway comprising various molecules, including MST 1/2 and LATS 1/2 ( 74 ). Dysregulation of YAP-/TAZ-mediated transcriptional activity has been observed in types of cancer, and the inhibition of YAP–/TAZ–TEAD interaction has been a promising treatment target for cancer.…”

Section: Discussionmentioning

confidence: 99%

KRAS G12C inhibitor combination therapies: current evidence and challenge

Miyashita,

Kato,

Hong

2024

Front. Oncol.

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Although KRAS G12C inhibitors have proven that KRAS is a “druggable” target of cancer, KRAS G12C inhibitor monotherapies have demonstrated limited clinical efficacy due to primary and acquired resistance mechanisms. Multiple combinations of KRAS G12C inhibitors with other targeted therapies, such as RTK, SHP2, and MEK inhibitors, have been investigated in clinical trials to overcome the resistance. They have demonstrated promising efficacy especially by combining KRAS G12C and EGFR inhibitors for KRAS G12C-mutated colorectal cancer. Many clinical trials of combinations of KRAS G12C inhibitors with other targeted therapies, such as SOS1, ERK, CDK4/6, and wild-type RAS, are ongoing. Furthermore, preclinical data have suggested additional promising KRAS G12C combinations with YAP/TAZ-TEAD inhibitors, FAK inhibitors, and farnesyltransferase inhibitors. The combinations of KRAS G12C inhibitors with immunotherapies and chemotherapies have also been investigated, and the preliminary results were reported. More recently, KRAS-targeted therapies not limited to KRAS G12C are being developed, potentially broadening the treatment landscape of KRAS-mutated cancers. Rationally combining KRAS inhibitors with other therapeutics is likely to play a significant role in future treatment for KRAS-mutated solid tumors.

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“…Indeed, both YAP and TAZ can bind chromatin remodeling complexes and influence chromatin accessibility [ 84 , 85 , 86 ]. YAP and TAZ also bind a long and growing list of transcription factors and proteins that can dramatically influence the transcriptional landscapes of cells and tissues [ 18 , 84 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD

Kanai,

Norton,

Stern

et al. 2024

Cancers

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Targeted therapies are effective cancer treatments when accompanied by accurate diagnostic tests that can help identify patients that will respond to those therapies. The YAP/TAZ-TEAD axis is activated and plays a causal role in several cancer types, and TEAD inhibitors are currently in early-phase clinical trials in cancer patients. However, a lack of a reliable way to identify tumors with YAP/TAZ-TEAD activation for most cancer types makes it difficult to determine which tumors will be susceptible to TEAD inhibitors. Here, we used a combination of RNA-seq and bioinformatic analysis of metastatic melanoma cells to develop a YAP/TAZ gene signature. We found that the genes in this signature are TEAD-dependent in several melanoma cell lines, and that their expression strongly correlates with YAP/TAZ activation in human melanomas. Using DepMap dependency data, we found that this YAP/TAZ signature was predictive of melanoma cell dependence upon YAP/TAZ or TEADs. Importantly, this was not limited to melanoma because this signature was also predictive when tested on a panel of over 1000 cancer cell lines representing numerous distinct cancer types. Our results suggest that YAP/TAZ gene signatures like ours may be effective tools to predict tumor cell dependence upon YAP/TAZ-TEAD, and thus potentially provide a means to identify patients likely to benefit from TEAD inhibitors.

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New Insights into YAP/TAZ-TEAD-Mediated Gene Regulation and Biological Processes in Cancer

Cited by 9 publications

References 267 publications

Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

Synergistic effect of PAK and Hippo pathway inhibitor combination in NF2-deficient Schwannoma

KRAS G12C inhibitor combination therapies: current evidence and challenge

Identification of a Gene Signature That Predicts Dependence upon YAP/TAZ-TEAD

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