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Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes., Dysregulation of the Hippo signaling is a frequent event in human malignancies, but the molecular mechanisms remain unclear. Here the authors show that in head and neck squamous carcinoma, FAT1 interacts with the Hippo signaling complex, resulting in the activation of core Hippo kinases and YAP1 inactivation.

While changes in heme oxygenase (HO-1) in lung cancer have already been reported, conflicting results were obtained for enzyme expression in human lung cancer specimens. Therefore, the aim of this work was to study HO-1 expression in a large collection of human lung cancer samples. For this purpose, we analyzed the expression of HO-1 in an organized tissue microarray (TMA) and investigated its correlation with clinicopathological data. Ninety-six percent of tumor samples were positive for HO-1, and the expression of HO-1 was significantly higher in cancerous than in non-cancerous tissues. Importantly, HO-1 expression correlated with advanced stages and lymph node involvement. Additionally, quantitative RT-PCR in 18 pairs of human lung carcinomas and their adjacent non-malignant tissues was performed. Our results demonstrate that HO-1 protein is upregulated in epithelial malignant cells in NSCLC and its expression is associated with higher stages of the disease. Additionally, different subcellular localization is observed between tumor and adjacent non-malignant tissues.

Squamous cell carcinomas of head and neck (HNSCC), which arise in the oral cavity, oropharynx, larynx, and hypopharynx, are a major public health concern. New therapeutic strategies to prevent and treat HNSCC patients are urgently needed. The epidermal growth factor receptor (EGFR) is overexpressed in up to 90% of HNSCC lesions (1,2) and is associated with unfavorable clinical outcome (3,4). Anti-EGFR targeted therapies have been shown to be effective in a variety of preclinical HNSCC models (5–8). Furthermore, in seminal clinical studies, cetuximab, a humanized IgG1 monoclonal antibody against the EGFR extracellular domain, prolonged the median overall survival and reduced disease progression in advanced HNSCC patients as part of combination therapies with radiation and chemotherapy (9,10). Based on these findings, cetuximab gained approval from the US Food and Drug Administration for use together with radiation or as a single agent in patients that failed to respond to platinum-based therapy, and for recurrent or metastatic HNSCC in combination with standard chemotherapy (10). However, the overall increased response of adding cetuximab to radiation and/or chemotherapy is approximately 10% to 20% (9,10), much lower than initially expected considering the high level of EGFR expression in HNSCC. Recent studies have identified multiple mechanisms of resistance to cetuximab, including EGFR mutations, overexpression of EGFR ligands, amplification or transactivation of HER family members or the MET receptor, and deregulated EGFR recycling (11–17), all of which could explain the intrinsic or acquired resistance to cetuximab in the clinic. EGFR regulates multiple intracellular signaling circuits, including the JAK/STAT3, RAS/MAPK, and PI3K/AKT/mTOR pathways (18–20). Among them, recent findings indicate that multiple genetic and epigenetic alterations converge on the persistent activation of PI3K/AKT/mTOR signaling in most HNSCC lesions (21–24). Thus, we asked here whether genetic alterations causing PI3K/AKT/mTOR activation can promote cetuximab resistance in HNSCC, and if so whether pharmacological inhibition of this signaling pathway represents a suitable target to prevent or overcome cetuximab resistance in HNSCC.