Impact of PI3K/AKT/mTOR pathway activation on the prognosis of patients with head and neck squamous cell carcinomas

// Darío García-Carracedo 1, * , Maria Ángeles Villaronga 2, * , Saúl Álvarez-Teijeiro 2 , Francisco Hermida-Prado 2 , Iñigo Santamaría 3 , Eva Allonca 2 , Laura Suárez-Fernández 2 , Maria Victoria Gonzalez 4 , Milagros Balbín 3 , Aurora Astudillo 4 , Pablo Martínez-Camblor 5 , Gloria H. Su 1, 6, 7, , Juan Pablo Rodrigo 2 , Juana María García-Pedrero 2 1 Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY, USA 2 Department of Otolaryngology, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain 3 Department of Molecular Oncology, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Universidad de Oviedo, Oviedo, Spain 4 Department of Pathology, Hospital Universitario Central de Asturias and Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain 5 Biostatistics Unit, Hospital Universitario Central de Asturias, Oviedo, Spain 6 Department of Pathology, Columbia University Medical Center, New York, NY, USA 7 Departments of Otolaryngology/Head and Neck Surgery, Columbia University Medical Center, New York, NY, USA * These authors have contributed equally to this work Correspondence to: Juan Pablo Rodrigo, email: juanpablo.rodrigo@sespa.princast.es Juana María García-Pedrero, email: juanagp@ficyt.es Keywords: HNSCC, prognosis, PIK3CA mutation, S6 phosphorylation, immunohistochemistry Received: September 17, 2015 Accepted: March 28, 2016 Published: April 23, 2016 ABSTRACT The PI3K/AKT/mTOR signaling pathway has emerged as one of the most frequently deregulated in head and neck squamous cell carcinomas (HNSCC). Numerous alterations of various upstream and downstream components have been described; however, their prognostic significance and impact on HNSCC patient survival remains to be established. This was addressed using an unbiased cohort of 93 consecutive and homogeneous surgically treated HNSCC patients and results confirmed in 432 HNSCC patients. Our findings reveal the high prevalence of S6 phosphorylation, a surrogate marker of mTORC1 activation, in HNSCC specimens (>70%) and, more importantly, demonstrate its relevance on clinical outcome. Phosphorylation of ribosomal protein S6 on either Ser235/236 or Ser240/244 was consistently and significantly correlated with favorable prognosis, although with differences depending on the tumor site. Thus, p-S6 expression was significantly correlated with better disease-specific survival specifically in the subgroup of laryngeal carcinoma patients ( P < 0.001). In addition, multivariate regression models revealed p-S6 to be an inverse and independent predictor of lymph-node metastasis ( P = 0.004) and distant metastasis ( P = 0.006). Taken together, this study unveils an unprecedented correlation of mTOR activation with improved clinical outcome in patients with laryngeal carcinomas and uncovers the potential of p-S6 expression as a good prognostic biomarker and an inverse predictor of lymph node and distant metastases. These results should be of broad interest as immunohistochemical detection of p-S6 may help to stratify patients and guide treatment decisions.