Targeting YAP/TAZ-TEAD signaling as a therapeutic approach in head and neck squamous cell carcinoma.

Genetic alterations in Hippo pathway and the consequent activation of YAP/TAZ-TEAD are frequently observed in HPV-negative head and neck squamous cell carcinoma (HNSCC) patients. These include loss-of-function mutation and/or copy number loss of FAT1, and amplification of YAP1 and WWTR1 (encoding TAZ), thus raising the possibility that HNSCC cells may be dependent on YAP/TAZ-TEAD-mediated transcriptional programs. In this regard, the recent development of small molecule TEAD inhibitors (smTEADi) provides an opportunity to therapeutically target Hippo pathway dysregulation in human malignancies. This prompted us to explore the potential benefit of pharmacologically targeting the YAP/TAZ-TEAD axis in this disease. Here, we provide the pre-clinical evidence for the antitumor activity of novel smTEADi, SW-682 in HPV-negative HNSCC. By the use of multiple complementary experimental approaches, including siRNA knockdown, expression of a genetically encoded TEAD inhibitor peptide (pTEADi), and SW-682, we revealed that disruption of YAP/TAZ-TEAD interaction suppresses YAP/TAZ-TEAD-dependent target gene transcription and growth of HNSCC tumors. HNSCC cells with genetic alterations in FAT1 were more sensitive to TEADi compared to FAT1-wild type cells. Mechanistically, TEADi suppressed cell cycle progression and promoted the expression of terminal differentiation gene programs, resulting in tumor growth inhibition. A HNSCC-specific TEADi target gene set was defined from RNA-seq data, which is highly expressed in HNSCC tissues and predicts poor prognosis of HPV-negative HNSCC patients. Our results underscore that YAP/TAZ-TEAD-mediated growth-promoting programs represent a vulnerability in HPV-negative HNSCC, thus providing a pre-clinical rationale for the future evaluation of YAP/TAZ-TEAD targeting strategies as a therapeutic approach for HPV-negative HNSCC patients.

Sato K ，Faraji F ，Cervantes-Villagrana RD ，Wu X ，Koshizuka K ，Ishikawa T ，Iglesias-Bartolome R ，Chen L ，Miliani de Marval PL ，Gwaltney SL ，Adler B ，Gutkind JS ... -  《-》

The Hippo effector TAZ promotes cancer stemness by transcriptional activation of SOX2 in head neck squamous cell carcinoma.

Li J ，Li Z ，Wu Y ，Wang Y ，Wang D ，Zhang W ，Yuan H ，Ye J ，Song X ，Yang J ，Jiang H ，Cheng J ... -  《Cell Death & Disease》

Nicotine enhances the stemness and tumorigenicity in intestinal stem cells via Hippo-YAP/TAZ and Notch signal pathway.

Cigarette smoking is a well-known risk factor inducing the development and progression of various diseases. Nicotine (NIC) is the major constituent of cigarette smoke. However, knowledge of the mechanism underlying the NIC-regulated stem cell functions is limited. In this study, we demonstrate that NIC increases the abundance and proliferative activity of murine intestinal stem cells (ISCs) in vivo and ex vivo. Moreover, NIC induces Yes-associated protein (YAP) /Transcriptional coactivator with PDZ-binding motif (TAZ) and Notch signaling in ISCs via α7-nicotinic acetylcholine receptor (nAchR) and protein kinase C (PKC) activation; this effect was not detected in Paneth cells. The inhibition of Notch signaling by dibenzazepine (DBZ) nullified the effects of NIC on ISCs. NIC enhances in vivo tumor formation from ISCs after loss of the tumor suppressor gene Apc, DBZ inhibited NIC-induced tumor growth. Hence, this study identifies a NIC-triggered pathway regulating the stemness and tumorigenicity of ISCs and suggests the use of DBZ as a potential therapeutic strategy for treating intestinal tumors.

Isotani R ，Igarashi M ，Miura M ，Naruse K ，Kuranami S ，Katoh M ，Nomura S ，Yamauchi T ... -  《eLife》

The Hippo pathway transcription factors YAP and TAZ play HPV-type dependent roles in cervical cancer.

Human papillomaviruses (HPVs) cause most cervical cancers and an increasing number of anogenital and oral carcinomas, with most cases caused by HPV16 or HPV18. HPV hijacks host signalling pathways to promote carcinogenesis. Understanding these interactions could permit identification of much-needed therapeutics for HPV-driven malignancies. The Hippo signalling pathway is important in HPV+ cancers, with the downstream effector YAP playing a pro-oncogenic role. In contrast, the significance of its paralogue TAZ remains largely uncharacterised in these cancers. We demonstrate that TAZ is dysregulated in a HPV-type dependent manner by a distinct mechanism to that of YAP and controls proliferation via alternative cellular targets. Analysis of cervical cancer cell lines and patient biopsies revealed that TAZ expression was only significantly increased in HPV18+ and HPV18-like cells and TAZ knockdown reduced proliferation, migration and invasion only in HPV18+ cells. RNA-sequencing of HPV18+ cervical cells revealed that YAP and TAZ have distinct targets, suggesting they promote carcinogenesis by different mechanisms. Thus, in HPV18+ cancers, YAP and TAZ play non-redundant roles. This analysis identified TOGARAM2 as a previously uncharacterised TAZ target and demonstrates its role as a key effector of TAZ-mediated proliferation, migration and invasion in HPV18+ cancers.

Patterson MR ，Cogan JA ，Cassidy R ，Theobald DA ，Wang M ，Scarth JA ，Anene CA ，Whitehouse A ，Morgan EL ，Macdonald A ... -  《Nature Communications》

YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis.

Yang W ，Zhang M ，Zhang TX ，Liu JH ，Hao MW ，Yan X ，Gao H ，Lei QY ，Cui J ，Zhou X ... -  《JCI Insight》