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Insights into recent findings and clinical application of YAP and TAZ in cancer

Nature Reviews Cancer volume 23, pages 512–525 (2023)Cite this article

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Abstract

Decades of research have mapped out the basic mechanics of the Hippo pathway. The paralogues Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), as the central transcription control module of the Hippo pathway, have long been implicated in the progression of various human cancers. The current literature regarding oncogenic YAP and TAZ activities consists mostly of context-specific mechanisms and treatments of human cancers. Furthermore, a growing number of studies demonstrate tumour-suppressor functions of YAP and TAZ. In this Review we aim to synthesize an integrated perspective of the many disparate findings regarding YAP and TAZ in cancer. We then conclude with the various strategies for targeting and treating YAP- and TAZ-dependent cancers.

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Fig. 1: YAP and TAZ regulation through canonical Hippo signalling and other pathways.
Fig. 2: Common modes of YAP and TAZ regulation.
Fig. 3: Rare fusions of YAP and TAZ in cancers.
Fig. 4: Therapeutically targeting YAP through TEAD.

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Acknowledgements

This work is supported by NIH grants GM51586 and CA268179 (K.-L.G.) and NIH/NCI T32 CA009523 (J.M.F.).

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  1. Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, CA, USA

    J. Matthew Franklin, Zhengming Wu & Kun-Liang Guan

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All authors researched data for the article. J.M.F. and K.-L.G. contributed substantially to discussion of the content, wrote the article, and reviewed and edited the manuscript before submission.

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Correspondence to Kun-Liang Guan.

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K.-L.G. is a co-founder of and has equity interest in Vivace Therapeutics. The other authors declare no competing interests.

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Glossary

Antisense technology

A method using engineered, non-coding oligonucleotides specific to an RNA to block downstream protein synthesis.

BRAF-V600E

A serine/threonine-protein kinase, part of the RAS–RAF–MEK–ERK signalling cascade; it is commonly mutated, such that the valine 600 is replaced by glutamic acid (V600E) to drive oncogenesis in many cancers.

cGAS–STING pathway

A component of the innate immune system responding to cytosolic DNA, composed of cyclic GMP–AMP (cGAMP) synthase and its downstream receptor stimulator of interferon genes (STING) to induce an inflammatory gene response.

Hepatomegaly

An overgrowth of liver that was found to be particularly sensitive to YAP activation.

NOTCH pathway

A signalling pathway that regulates cell-fate decisions and tissue homeostasis through interaction of transmembrane Notch receptors (NOTCH1–4) on one cell and the ligands of the Delta-like and Jagged families on the opposing neighbouring cell.

Palmitoylation

A post-translational modification whereby palmitic acid is covalently bonded to a cysteine residue or, less frequently, a serine or threonine residue.

Programmed cell death 1 ligand 1

(PDL1). A transmembrane protein expressed on cancer cells to supress the immune response by binding to its receptor PD1, commonly expressed on T cells; it is a major target of current cancer immunotherapies.

WNT pathway

A developmental signalling pathway consisting of the WNT family of extracellular ligands, the Frizzled and lipoprotein receptor-related protein (LRP) family of cell surface receptors, the cytosol localized Dishevelled family and nuclear mediator β-catenin.

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Franklin, J.M., Wu, Z. & Guan, KL. Insights into recent findings and clinical application of YAP and TAZ in cancer. Nat Rev Cancer 23, 512–525 (2023). https://doi.org/10.1038/s41568-023-00579-1

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