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Objectives-No reliable molecular biomarker is currently available for clinical application in the management of head and neck cancer patients. The AKT/MTOR pathway is activated in 90-100% of HNSCC and could be promising biomarkers closely linked to cancer incidence.Methods-Oral mucosa from non-cancer patients were compared to HNSCC tumors and junctional zone mucosa. The candidate biomarkers MTOR, AKT, 4EBP1, and S6 kinase, signaling components upstream and downstream of MTOR that appear dysregulated in HNSCC were evaluated using immunohistochemistry (IHC) and western blot.Results-Expression of phosphorylated AKT and phosphorylated MTOR were significantly higher in cancer patient tumors compared to non-cancer oral mucosa samples (p=0.004 and p=0.026 respectively) by western. pMTOR and p4EBP1 expression were higher in patient junctional zones compared to tumors (p=0.017 and p=0.022 respectively) and no difference in p-AKT or p-S6 expression in HNSCC patients' junctional zone compared to tumors. IHC demonstrated p-MTOR expression was 81.9% sensitive and 100% specific in differentiating cancer from non-cancer mucosa, while p-4EBP1 expression by IHC was only 50.0% sensitive and 95.5% specific in differentiating normal mucosa from HNSCC (p<0.01).Conclusions-Phosphorylated MTOR appears to be a reliable biomarker by both western (p=0.026) and IHC in human head and neck cancer (p<0.001). Moreover, phosphorylated AKT, which is immediately upstream of MTOR, is a potential biomarker that should be further studied. Clinical trials with MTOR inhibitors are being evaluated for HNSCC, and selecting patients that are likely to respond to these inhibitors requires identifying and validating predictive biomarkers of response.

BACKGROUND After long-term androgen deprivation therapy, 25-30% prostate cancer (PCa) acquires an aggressive neuroendocrine (NE) phenotype. Dysregulation of YAP1, a key transcription coactivator of the Hippo pathway, has been related to cancer progression. However, its role in neuroendocrine prostate cancer (NEPC) has not been assessed. METHODS Immunohistochemistry was used to evaluate YAP1 protein levels during PCa initiation and progression. YAP1 knockdown and luciferase reporter assays were used to evaluate the ability of YAP1 to modulate Wnt/beta-Catenin signaling. RESULTS YAP1 expression was present in the basal epithelial cells in benign prostatic tissues, lost in low grade PCa, but elevated in high grade prostate adenocarcinomas. Interestingly, the expression of YAP1 was reduced/lost in both human and mouse NEPC. Finally, YAP1 knockdown in PCa cells activates Wnt/beta-Catenin signaling, which has been implicated in NE differentiation of PCa, supporting a functional involvement of the loss of YAP1 expression in NEPC development. CONCLUSIONS The expression of YAP1 is elevated in high grade prostate adenocarcinomas while lost in NEPC. Reduced YAP1 activates Wnt/beta-Catenin signaling in PCa cells. These results suggest that when applied to PCa patients, YAP1 inhibitors shall be used with caution.