Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine

Barry, Evan; Simov, Vladimir; Valtingojer, Iris; Venier, Olivier

doi:10.3390/cells10102715

Cited by 51 publications

(53 citation statements)

References 120 publications

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“…Pharmacological inhibitors of YAP1-TEAD activity may be helpful beyond tumors with Hippo-YAP1 alterations and could be employed for a broader set of combination treatment strategies. Drug discovery efforts for the identification of YAP1-TEAD inhibitors have indeed progressed over recent years (reviewed in [ 48 ]). In particular, compounds targeting the allosteric lipid pocket of TEAD proteins have been put forward with a set of molecules in preclinical development [ 15 , 39 ], and the first compounds from Vivace Therapeutics and Ikena Oncology entered clinical trials last year and early this year, respectively ( [ 41 ], NCT04665206, NCT05228015).…”

Section: Discussionmentioning

confidence: 99%

YAP1 is essential for malignant mesothelioma tumor maintenance

et al. 2022

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Malignant pleural mesothelioma, a tumor arising from the membrane covering the lungs and the inner side of the ribs, is a cancer in which genetic alterations of genes encoding proteins that act on or are part of the Hippo-YAP1 signaling pathway are frequent. Dysfunctional Hippo signaling may result in aberrant activation of the transcriptional coactivator protein YAP1, which binds to and activates transcription factors of the TEAD family. Recent studies have associated elevated YAP1 protein activity with a poor prognosis of malignant mesothelioma and its resistance to current therapies, but its role in tumor maintenance is unclear. In this study, we investigate the dependence of malignant mesothelioma on YAP1 signaling to maintain fully established tumors in vivo. We show that downregulation of YAP1 in a dysfunctional Hippo genetic background results in the inhibition of YAP1/TEAD-dependent gene expression, the induction of apoptosis, and the inhibition of tumor cell growth in vitro. The conditional downregulation of YAP1 in established tumor xenografts leads to the inhibition of YAP1-dependent gene transcription and eventually tumor regression. This effect is only seen in the YAP1-activated MSTO-211H mesothelioma xenograft model, but not in the Hippo-independent HCT116 colon cancer xenograft model. Our data demonstrate that, in the context of a Hippo pathway mutated background, YAP1 activity alone is enough to maintain the growth of established tumors in vivo, thus validating the concept of inhibiting the activated YAP1-TEAD complex for the treatment of malignant pleural mesothelioma patients.

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Section: Discussionmentioning

confidence: 99%

YAP1 is essential for malignant mesothelioma tumor maintenance

et al. 2022

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“…The majority of the identified small molecule YAP/TAZ-TEAD disruptors bind to the central pocket of TEAD and therefore have an allosteric mode of action [ 16 , 40 ]. Some of the molecules, such as MGH-CP1 and others, bind non-covalently, whereas others like TEAD-347 and MYF-01-037 are covalent ligands [ 41 – 44 ].…”

Section: Discussionmentioning

confidence: 99%

Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex

et al. 2022

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Disrupting the formation of the oncogenic YAP/TAZ-TEAD transcriptional complex holds substantial therapeutic potential. However, the three protein interaction interfaces of this complex cannot be easily disrupted using small molecules. Here, we report that the pharmacologically active small molecule aurintricarboxylic acid (ATA) acts as a disruptor of the TAZ-TEAD complex. ATA was identified in a high-throughput screen using a TAZ-TEAD AlphaLISA assay that was tailored to identify disruptors of this transcriptional complex. We further used fluorescence polarization assays both to confirm disruption of the TAZ-TEAD complex and to demonstrate that ATA binds to interface 3. We have previously shown that cell-based models that express the oncogenic TAZ-CAMTA1 (TC) fusion protein display enhanced TEAD transcriptional activity because TC functions as an activated form of TAZ. Utilizing cell-based studies and our TC model system, we performed TC/TEAD reporter, RNA-Seq, and qPCR assays and found that ATA inhibits TC/TEAD transcriptional activity. Further, disruption of TC/TEAD and TAZ/TEAD interaction by ATA abrogated anchorage-independent growth, the phenotype most closely linked to dysregulated TAZ/TEAD activity. Therefore, this study demonstrates that ATA is a novel small molecule that has the ability to disrupt the undruggable TAZ-TEAD interface.

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“…These challenges point towards drugging the YAP/TAZ transcriptional coactivators and TEADs. As reviewed elsewhere [ 10 , 62 ], there has been tremendous progress in the development of therapeutic approaches to disrupt YAP/TAZ–panTEAD interaction directly or by allosterically inhibiting TEAD palmitoylation. Since YAP/TAZ/TEADs also play a pivotal role in transcriptional addiction, targeting the transcriptional dependencies in YAP-driven cancers is another appealing strategy for therapeutic intervention.…”

Section: Outstanding Questionsmentioning

confidence: 99%

Transcriptional Regulation of the Hippo Pathway: Current Understanding and Insights from Single-Cell Technologies

Paul¹,

Xie²,

Yao³

et al. 2022

Cells

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The Hippo pathway regulates tissue homeostasis in normal development and drives oncogenic processes. In this review, we extensively discuss how YAP/TAZ/TEAD cooperate with other master transcription factors and epigenetic cofactors to orchestrate a broad spectrum of transcriptional responses. Even though these responses are often context- and lineage-specific, we do not have a good understanding of how such precise and specific transcriptional control is achieved—whether they are driven by differences in TEAD paralogs, or recruitment of cofactors to tissue-specific enhancers. We believe that emerging single-cell technologies would enable a granular understanding of how the Hippo pathway influences cell fate and drives oncogenic processes, ultimately allowing us to design better pharmacological agents against TEADs and identify robust pharmacodynamics markers of Hippo pathway inhibition.

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Recent Therapeutic Approaches to Modulate the Hippo Pathway in Oncology and Regenerative Medicine

Cited by 51 publications

References 120 publications

YAP1 is essential for malignant mesothelioma tumor maintenance

YAP1 is essential for malignant mesothelioma tumor maintenance

Aurintricarboxylic acid is a canonical disruptor of the TAZ-TEAD transcriptional complex

Transcriptional Regulation of the Hippo Pathway: Current Understanding and Insights from Single-Cell Technologies

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