Modeling YAP fusions: a paradigm for investigating rare cancers?

In this Outlook, Sahebjam and Gilbert discuss a study published in the July issue of Genes & Development from Szulzewsky et al., who show that TEAD-dependent YAP1 activity by either the loss of the NF2 gene or YAP1-MAML2 fusion is an oncogenic process promoting meningioma tumorigenesis.

Abstract

Loss of the NF2 tumor suppressor gene is a common finding in meningiomas, and more recently YAP1 fusions have been found in a subset of pediatric NF2 wild-type meningiomas. In the previous issue of Genes & Development, Szulzewsky and colleagues (pp. 857–870) showed that TEAD-dependent YAP1 activity by either the loss of the NF2 gene or YAP1-MAML2 fusion is an oncogenic process promoting meningioma tumorigenesis. Furthermore, pharmacological inhibition of YAP1-TEAD resulted in antitumor activity in both YAP1 fusion-positive and NF2 mutant meningiomas. Together, these data indicate that disruption of the YAP1-TEAD interaction raises a potential therapeutic option for these tumors that requires future investigation.

Loss of the NF2 tumor suppressor gene is found in up to two-thirds of the meningiomas that are the most common primary central nervous system (CNS) tumors in adults. The role of biallelic NF2 gene inactivation in initiation and malignant progression of meningiomas has been confirmed by using genetically engineered mouse models such as those with arachnoidal cell Cre-mediated excision of Nf2 exon 2 (Kalamarides et al. 2002; Peyre et al. 2013). Further studies have suggested that loss of Merlin, the NF2 gene product upstream of the Hippo cascade, results in activation of YAP1, which functions as an oncogene by promoting meningioma tumorigenesis (Baia et al. 2012). YAP1 is a transcriptional coactivator that is implicated in cancer initiation and progression via its interaction with TEAD transcription factors (Varelas 2014). Baia et al. (2012) have demonstrated that transient knockdown of YAP1 in NF2 mutant meningioma cells leads to impaired cell proliferation and migration. Additionally, overexpression of YAP1 in nontransformed arachnoidal cells results in development of tumors in nude mice, confirming the oncogenic role of YAP1 activation (Baia et al. 2012).

Recently, gene fusions involving the N-terminal regions of YAP1 have been found in a subset of pediatric NF2 wild-type meningiomas. These meningiomas resembled NF2 mutant tumors by DNA methylation-based classification, and the YAP1-MAML2 was the most common fusion, accounting for seven out of nine patient tumor samples. Although these alterations seem to act as an alternative to NF2 inactivation, their oncogenic role in the development of pediatric NF2 wild-type meningiomas and the overall biology of this group of tumors are not known (Sievers et al. 2020).

In the previous issue of Genes & Development, Szulzewsky et al. (2022) reported an elegant study that significantly expands our understanding of the deregulation of the Hippo pathway in meningioma formation. The investigators began by comparing gene expression patterns of human YAP1 fusion-positive meningiomas with the more common meningiomas, and specifically NF2 mutant meningiomas. Human NF2 wild-type YAP1 fusion-positive meningiomas resembled NF2 mutant meningiomas by gene expression, both on a global level and in YAP1-regulated genes. To confirm that human YAP1 fusion-positive meningiomas and NF2 mutant meningiomas exert increased levels of YAP signaling, the investigators analyzed the expression of several direct YAP1 target genes. Both human YAP1 fusion-positive and NF2 mutant meningiomas showed higher expression levels of several canonical YAP1 target genes. Interestingly, YAP1-related gene expression signatures were largely similar between the YAP1 fusion-positive and NF2 mutant meningiomas. Then, to study the oncogenic function of YAP1-MAML2, Szulzewsky et al. (2022) used a RCAS/tv-a mouse model that has successfully recapitulated the pathobiology of other CNS tumors in immunocompetent mice (Szulzewsky et al. 2020). Expression of YAP1-MAML2 in the RCAS/tv-a mouse model induced formation of meningioma-like tumors resembling human YAP1 fusion-positive and NF2 mutant meningiomas by gene expression, suggesting that the YAP1-MAML2 fusion is the oncogenic driver in YAP1-MAML2-positive meningiomas. Furthermore, the investigators showed that, like several other YAP1 fusion proteins, YAP1-MAML2 is constitutively localized to the nucleus and exerts its oncogenic function via interaction with TEAD transcription factors. It is not yet known whether disrupting the YAP1-TEAD complex will be an effective treatment strategy for YAP1 fusion-positive and NF2 mutant meningiomas. However, both YAP1 fusion-positive and NF2 mutant meningiomas responded to pharmacological inhibition of YAP1-TEAD, further confirming the central role of Hippo pathway deregulation in meningioma tumorigenesis.

The study by Szulzewsky et al. (2022) expands our knowledge about the critical role of TEAD-dependent YAP1 activity as an oncogenic process promoting meningioma tumorigenesis. It indicates that YAP1 activity by either the loss of the NF2 tumor suppressor gene or YAP1-MAML2 fusion is a central mechanism of meningioma formation and progression. Moreover, it provides a potential future direction for development of therapeutics for malignant meningiomas, an area of unmet need. Currently, there is no effective treatment for recurrent meningiomas that have progressed after surgical resection and radiotherapy. Importantly, this work clearly demonstrated that YAP1 fusion-positive and NF2 mutant meningiomas will be resistant to upstream Hippo pathway-mediated inhibition and explains the lack of significant clinical benefit from previous efforts to target these upstream signaling pathways. More recently, a new class of small molecule TEAD inhibitors has entered clinical investigation. These agents bind TEAD noncovalently in the central hydrophobic pocket and prevent its autopalmitoylation and interaction with the YAP/TAZ transcription coactivators (Chan et al. 2016; Tang et al. 2021). In the current study and previous experiments on NF2-deficient mesothelioma models, TEAD autopalmitoylation inhibitors have demonstrated selective YAP/TAZ-TEAD inhibition in vitro and in vivo, antitumor activity, and excellent oral bioavailability in tumors with TEAD-dependent YAP1 activity (Tang et al. 2021). These data support the further clinical evaluation of TEAD palmitoylation inhibitors in tumors with NF2 mutation or YAP1 fusion.

Moreover, this study emphasizes the significance of using genetically engineered mouse models that accurately recapitulate genetic alterations found in CNS tumors. Over the past decades, multiple novel treatment modalities that had initially shown therapeutic activity in various animal models of CNS tumors failed to show antitumor efficacy in large clinical trials. This underscores the significant limitations of many of these models to accurately reflect the biological properties of the human tumors. RCAS/tv-a mouse models have successfully recapitulated human YAP1 fusion-positive tumors in immunocompetent mice and can therefore provide an insight into specific mechanisms of action and pharmacological properties of novel agents targeting YAP1-TEAD transcriptional activity. Although blocking YAP1-TEAD interactions with small molecule TEAD palmitoylation inhibitors appears to be a promising therapeutic strategy, the development of resistance is inevitable and the mechanisms of resistance to therapy remain to be determined. In this context, the models created by Szulzewsky et al. (2022) can be used to further investigate these mechanisms of escape and identify strategies to interfere with the development of resistance.

In summary, this study sheds light on the mechanism of meningioma tumorigenesis and highlights TEAD-dependent YAP1 activity by either the loss of NF2 tumor suppressor gene or YAP1-MAML2 fusion as an oncogenic factor. Disruption of the YAP1-TEAD interaction raises a potential therapeutic option for these tumors that requires future investigation. More importantly, translation of preclinical testing of novel agents in the YAP1 fusion model into human clinical trials with prediction of response and treatment resistance will facilitate the discovery of novel therapies, particularly for rare cancers where large or multiarm clinical trials are not feasible.