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.
Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: J. Silvio Gutkind reports consulting fees from Radionetics Oncology, BTB Therapeutics, Pangea Therapeutics, and io9 and is the founder of Kadima Pharmaceuticals, all unrelated to the current study. Lei Chen, Paula L. Miliani de Marval, Stephen L. Gwaltney and Benjamin Adler are employees of SpringWorks Therapeutics.
(Copyright © 2025. Published by Elsevier B.V.)