Targeting Transcriptional Enhanced Associate Domains (TEADs)

Gibault, Floriane; Sturbaut, Manon; Bailly, Fabrice; Melnyk, Patricia; Cotelle, Philippe

doi:10.1021/acs.jmedchem.7b00879

Cited by 72 publications

(65 citation statements)

References 67 publications

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“…Other compounds reported to target the Hippo pathway by various direct or indirect measures have recently been reviewed elsewhere and represent an area of active investigation [65].…”

Section: Targeting the Hippo Pathway In Cancermentioning

confidence: 99%

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

Calses¹,

Crawford²,

Lill³

et al. 2019

Trends in Cancer

299

220

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The Hippo pathway remains a central focus in both basic and translational research and is a key modulator of developmental biology. Dysregulation of the pathway is associated with a plethora of human cancers and there are multiple efforts to target key components of the pathway for disease intervention. In this review, we briefly highlight the latest research advances around the core components of the Hippo pathway in cancer. More specifically, we discuss several genetic aberrations of these factors as mechanisms for the development of cancers, including genetic amplification, deletion, and gene fusions. Additionally, we highlight the role of the Hippo pathway in cancer therapy resistance and tumor immunogenicity. Last, we summarize the ongoing efforts to target the pathway in cancers. The Hippo Pathway The Hippo pathway is a highly conserved signaling pathway across higher-order vertebrates that modulates key target genes to regulate a multitude of biological processes including cellular proliferation, survival, differentiation, cellular fate determination, organ size, and tissue homeostasis (Figure 1). At the core of the pathway are serine/threonine kinases, sterile 20-like kinase 1/2 (MST1/2), and large tumor suppressor 1/2 (LATS1/2). Recently, MAP4K and TAOK kinases have been shown to directly phosphorylate LATS1/2, thus acting in parallel with MST1/2 [1]. These kinases, along with the adaptor proteins, Salvador homolog 1 (SAV1) and MOB kinase activator 1A/B (MOB1A/B), phosphorylate and inhibit downstream effector proteins, Yesassociated protein (YAP1), and its paralog transcriptional coactivator with PDZ-binding motif (TAZ) (also known as WWTR1) and sequestrates them in the cytoplasm by binding to 14-3-3 proteins [2]. Notably, the tumor suppressor neurofibromin 2 (NF2) (also known as Merlin) participates upstream of these kinases to inhibit YAP and TAZ activity by promoting the activation of the pathway. Additional phosphorylation of YAP/TAZ leads to proteasome-mediated degradation facilitated by binding to β-TrCP [3,4]. Such regulation prevents YAP/TAZ from accumulating in the nucleus and from binding to a family of sequence-specific transcription factors called TEA DNA-binding proteins (TEAD1-4) that mediate proliferative and prosurvival genes such as CTGF, CRY61, BIRC5, ANKRD1, and AXL (Figure 2). Besides TEADs, YAP/TAZ also cooperates with RUNT-related transcription factors (RUNX1 and 2), T-box transcription factor 5 (TBX5), and SMADs as among others [2,5]. Hippo Pathway Deregulation in Cancer Overexpression of Hippo Pathway Effector Proteins Aberration of the Hippo pathway is associated with the hallmarks of oncogenesis and, more recently, has been linked to other cellular processes such as regulation of T cell functionality [6]. These hallmarks include the induction of hyperproliferation, cellular invasion, and metastasis, as well as a role in cancer cell maintenance and chemotherapeutic resistance mechanisms. Analysis of over 9000 tumors showed that YAP and TAZ are frequently amplified in head and nec...

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“…Other compounds reported to target the Hippo pathway by various direct or indirect measures have recently been reviewed elsewhere and represent an area of active investigation [65].…”

Section: Targeting the Hippo Pathway In Cancermentioning

confidence: 99%

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

Calses¹,

Crawford²,

Lill³

et al. 2019

Trends in Cancer

299

220

View full text Add to dashboard Cite

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“…The experimental evidence discussed above suggests that YAP/TAZ activation, which occurs in many human cancer types, is pro-tumorigenic and pro-metastatic. Given this, there is great enthusiasm regarding YAP/TAZ-TEAD as targets for anticancer therapies and several recent reviews have discussed this [ 28 , 29 , 32 , 33 , 182 , 183 , 184 , 185 ]. Although YAP and TAZ activity is often elevated in cancer cells, their activity is typically low in resting tissue, and mouse models suggest that YAP and TAZ are largely dispensable in several adult organs [ 104 , 186 , 187 ].…”

Section: Therapeutic Potential Of Targeting Yap/taz-tead In Cancermentioning

confidence: 99%

“…It may also be possible to target the TEADs [ 202 ]. The four TEADs share significant homology within the N -terminal DNA-binding domain and the C -terminal YAP/TAZ/VglL binding domain [ 185 ]. The structures for the DNA-binding domains have been solved [ 203 , 204 , 205 , 206 , 207 ], but there are no existing drugs known to target this region [ 185 ].…”

Section: Therapeutic Potential Of Targeting Yap/taz-tead In Cancermentioning

confidence: 99%

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Warren

Xiao

2018

Cancers

139

131

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Yes-Associated Protein (YAP) and Transcriptional Co-activator with PDZ-binding Motif (TAZ) have both emerged as important drivers of cancer progression and metastasis. YAP and TAZ are often upregulated or nuclear localized in aggressive human cancers. There is abundant experimental evidence demonstrating that YAP or TAZ activation promotes cancer formation, tumor progression, and metastasis. In this review we summarize the evidence linking YAP/TAZ activation to metastasis, and discuss the roles of YAP and TAZ during each step of the metastatic cascade. Collectively, this evidence strongly suggests that inappropriate YAP or TAZ activity plays a causal role in cancer, and that targeting aberrant YAP/TAZ activation is a promising strategy for the treatment of metastatic disease. To this end, we also discuss several potential strategies for inhibiting YAP/TAZ activation in cancer and the challenges each strategy poses.

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“…Based on binding studies and a crystal structure, the mutated residues that slowed tumor growth were at positions critical for binding to the minor and major groove of the MCAT DNA sequence [ 33 ]. These regions have also been proposed as two of three potentially sites of therapeutic targets on the DBD [ 67 ]. Due to the high sequence conservation of the DBD ( Figure 2 ), inhibitors that target this region would be pan-specific and provide a useful tool for further understanding TEAD biology.…”

Section: Tead As a Therapeutic Targetmentioning

confidence: 99%

Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

Holden¹,

Cunningham²

2018

Cancers

139

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The Hippo pathway is a critical transcriptional signaling pathway that regulates cell growth, proliferation and organ development. The transcriptional enhanced associate domain (TEAD) protein family consists of four paralogous transcription factors that function to modulate gene expression in response to the Hippo signaling pathway. Transcriptional activation of these proteins occurs upon binding to the co-activator YAP/TAZ whose entry into the nucleus is regulated by Lats1/2 kinase. In recent years, it has become apparent that the dysregulation and/or overexpression of Hippo pathway effectors is implicated in a wide range of cancers, including prostate, gastric and liver cancer. A large body of work has been dedicated to understanding the therapeutic potential of modulating the phosphorylation and localization of YAP/TAZ. However, YAP/TAZ are considered to be natively unfolded and may be intractable as drug targets. Therefore, TEAD proteins present themselves as an excellent therapeutic target for intervention of the Hippo pathway. This review summarizes the functional role of TEAD proteins in cancer and assesses the therapeutic potential of antagonizing TEAD function in vivo.

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Targeting Transcriptional Enhanced Associate Domains (TEADs)

Cited by 72 publications

References 67 publications

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

Hippo Pathway in Cancer: Aberrant Regulation and Therapeutic Opportunities

YAP/TAZ Activation as a Target for Treating Metastatic Cancer

Targeting the Hippo Pathway and Cancer through the TEAD Family of Transcription Factors

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