RESUMEN
Purpose: The primary cause of death due to head and neck squamous cell carcinoma (HNSCC) is local treatment failure. The goal of this study was to examine this phenomenon using an unbiased approach.Experimental Design: We utilized human papilloma virus (HPV)-negative cell lines rendered radiation-resistant (RR) via repeated exposure to radiation, a panel of HPV-negative HNSCC cell lines and three cohorts of HPV-negative HNSCC tumors (n = 68, 97, and 114) from patients treated with radiotherapy and subjected to genomic, transcriptomic, and proteomic analysis.Results: RR cell lines exhibited upregulation of several proteins compared with controls, including increased activation of Axl and PI3 kinase signaling as well as increased expression of PD-L1. Additionally, inhibition of either Axl or PI3 kinase led to decreased PD-L1 expression. When clinical samples were subjected to RPPA and mRNA expression analysis, PD-L1 was correlated with both Axl and PI3K signaling as well as dramatically associated with local failure following radiotherapy. This finding was confirmed examining a third cohort using immunohistochemistry. Indeed, tumors with high expression of PD-L1 had failure rates following radiotherapy of 60%, 70%, and 50% compared with 20%, 25%, and 20% in the PD-L1-low expression group (P = 0.01, 1.9 × 10-3, and 9 × 10-4, respectively). This finding remained significant on multivariate analysis in all groups. Additionally, patients with PD-L1 low/CD8+ tumor-infiltrating lymphocytes high had no local failure or death due to disease (P = 5 × 10-4 and P = 4 × 10-4, respectively).Conclusions: Taken together, our data point to a targetable Axl-PI3 kinase-PD-L1 axis that is highly associated with radiation resistance. Clin Cancer Res; 23(11); 2713-22. ©2017 AACR.
Asunto(s)
Antígeno B7-H1/genética , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/radioterapia , Fosfatidilinositol 3-Quinasas/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Tirosina Quinasas Receptoras/genética , Anciano , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Femenino , Regulación Neoplásica de la Expresión Génica/efectos de la radiación , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Linfocitos Infiltrantes de Tumor , Masculino , Persona de Mediana Edad , Papillomaviridae/patogenicidad , Proteómica , ARN Mensajero/efectos de la radiación , Tolerancia a Radiación/genética , Transducción de Señal/efectos de la radiación , Tirosina Quinasa del Receptor AxlRESUMEN
BACKGROUND: The purpose of this study was to present the results of our investigation of malic enzyme (ME) expression and the induction of senescence in head and neck squamous cell carcinoma (HNSCC). METHODS: P53, ME1, ME2, and aspects of cellular metabolism, such as reactive oxygen species (ROS) were investigated in HNSCC cell lines. RESULTS: Both metformin and ionizing radiation inhibited the expression of ME2, but not ME1, in HNSCC. Knockdown of ME1 or ME2 potentiated therapy-induced senescence in HNSCC cells regardless of p53 status, and led to increased p21 and generation of ROS. Therapy-induced senescence in ME-depleted cells was blocked by the antioxidant N-acetyl cysteine. Finally, high expression of ME2 was associated with poorer overall survival (OS) in patients with HNSCC. CONCLUSION: Depletion of ME enhances therapy-induced senescence and seems driven largely by ROS. ME2 expression in HNSCC may be associated with poor outcome, providing a possible link between therapy-induced senescence and patient outcome, and indicating a potential therapeutic benefit of targeting ME2. © 2015 Wiley Periodicals, Inc. Head Neck 38: E934-E940, 2016.
