The Hippo pathway in cancer: YAP/TAZ and TEAD as therapeutic targets in cancer

Abstract

Tumorigenesis is a highly complex process, involving many interrelated and cross-acting signalling pathways. One such pathway that has garnered much attention in the field of cancer research over the last decade is the Hippo signalling pathway. Consisting of two antagonistic modules, the pathway plays an integral role in both tumour suppressive and oncogenic processes, generally via regulation of a diverse set of genes involved in a range of biological functions. This review discusses the history of the pathway within the context of cancer and explores some of the most recent discoveries as to how this critical transducer of cellular signalling can influence cancer progression. A special focus is on the various recent efforts to therapeutically target the key effectors of the pathway in both preclinical and clinical settings.

Keywords: AlphaFold; Cancer; Hippo pathway; Immuno-oncology; Mesothelioma; Sarcoma.

Figure 1. The Hippo pathway consists of distinct oncogenic and tumour suppressive modules

Schematic of the core Hippo pathway, including the generally tumour suppressive core kinase module (highlighted in blue) and tumorigenic transcriptional module (highlighted in red). A selection of upstream, regulatory components are additionally included. Protein products of genes frequently mutated in various specific tumour types are shown in darker colours. Note that MST1/2 are encoded by STK4/3 respectively and TAZ by WWTR1.

Figure 2. YAP/TAZ fusion partners and associated cancers

Protein schematics showing the structures and domains of YAP/TAZ proteins (left) and common fusion partners in specific cancers (right). The location of frequent fusion breaks are denoted (red dashed lines), with common fusions and associated cancer types highlighted in red resulting in chimeric transcription factors. TAZ is encoded by WWTR1. Abbreviations: AD, acidic domain; ANK, ankyrin repeat region; bHLH, basic helix–loop–helix; CC, coiled-coil domain; CG-1, CG-1 DNA-binding domain; Glut, glutamine-rich region; IQ, IQ calmodulin-binding motif; LZ, leucine zipper; MAML, mastermind-like domain; PDZ, PDZ-binding domain; Prol, proline-rich region; ser, serine-rich region; TIG, transcription factor immunoglobulin domain.

Figure 3. Intrinsic disorder of YAP and TAZ

(A) Schematic of YAP protein structure, overlaid on to AlphaFold prediction expected position error of folded domains. Darker colours show a higher confidence in predicted relationship between residues. In general, a high level of predicted error persists throughout the various YAP domains, with just WW and CC domains exhibiting high levels of structural predictability. (B) Schematic of TAZ, as in (A), highlighting the high levels of intrinsic disorder that exists outside WW and CC domains. (C) Schematic of TEAD4, as in (A), with a higher degree of confidence in protein structure prediction observed throughout, as compared with YAP and TAZ proteins, suggesting a higher degree of structural order in TEAD4. Abbreviations: CC, coiled-coil domain; PDZ, PDZ-binding domain; TEA, TEA domain; YBD, YAP-binding domain.

Figure 4. Implementing YAP levels as prognostic indicator of YAP activity

Scatter-plot showing correlation between total YAP levels and levels of pYAP (S127) in patients across a range of cancer types. A strong and significant positive correlation exists between the levels of the two proteins, indicating that in patients with high levels of pYAP (S127), a concurrent increase in total YAP levels is observed. Points shown comprise RPPA data across the pan-cancer dataset (obtained from the Genomic Data Comms portal; https://gdc.cancer.gov/), normalised across cancer subtypes (level 4). Correlation coefficients and P-values were determined via Spearman method.