Targeting the Hippo-YAP/TEAD Signaling Network in Head and Neck Cancer

Summary Despite recent advances in treatment, the overall mortality for head and neck squamous cell carcinoma (HNSCC) remains high, and current treatment regimens incur significant long-term morbidity. Immune checkpoint blockade (ICB) therapies have revolutionized HNSCC treatment, but <30% of HNSCC patients respond to these immunotherapies. This highlights the urgent need to identify novel therapeutic options for HNSCC to improve mortality, reduce morbidity, and enhance the response rate of ICB. The mechanisms by which dysregulated oncogenic signaling drives HNSCC initiation, immune escape, progression, and metastasis remain incompletely defined, limiting our ability to develop effective precision prevention and treatment strategies. In this regard, our laboratory contributed to the discovery that the persistent activation of the Hippo- YAP/TEAD signaling network is one of the most frequent dysregulated oncogenic mechanisms in HNSCC. By combining the use of genetically engineered mouse models and single-cell transcriptomics, we have recently shown that when combined with p53 disruption, YAP activation is sufficient to reprogram epithelial progenitor cells into cancer-initiating cells and to establish an immune-evasive tumor microenvironment (TME), thereby promoting HNSCC progression. These findings, together with the recent development of clinically active TEAD inhibitors (TEADi) that disrupt Hippo-YAP/TEAD function, create a timely and unique opportunity to target TEAD for therapeutic benefit. Our premise is that aberrant Hippo-YAP/TEAD activation integrates proliferative signaling and immune escape programs, driving HNSCC initiation and progression. Our central hypothesis is that the Hippo-YAP/TEAD signaling network represents a major HNSCC oncogenic and immune escape driver, and that in turn, the disruption of Hippo-YAP/TEAD signaling will provide a novel therapeutic approach to reduce the growth of HNSCC lesions and dismantle their immune evasive mechanisms, thereby establishing an immune permissive TME and increasing the response to ICB. This will be explored in our two aims: 1) exploiting synthetic lethal and gene interaction networks to expose druggable systems vulnerabilities upon Hippo-YAP/TEAD blockade; and 2) to establish the impact of targeting the Hippo-YAP/TEAD signaling network on the immune TME at the single-cell and spatial resolution, aimed at increasing the response to ICB. Ultimately, we aim to develop novel rational combinations of targeted and immune therapies for HNSCC patients. Project Number: 1R01CA314197-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Jorge Silvio Gutkind (+1 co-PI) | Institution: UNIVERSITY OF CALIFORNIA, SAN DIEGO, LA JOLLA, CA | Award Amount: $694,643 | Activity Code: R01 | Study Section: Mechanisms of Cancer Therapeutics B Study Section[MCTB] View on NIH RePORTER: https://reporter.nih.gov/project-details/11392048