The Differential Impact of SRC Expression on the Prognosis of Patients with Head and Neck Squamous Cell Carcinoma

Abstract

Aberrant SRC expression and activation is frequently detected in multiple cancers, and hence, targeting SRC has emerged as a promising therapeutic strategy. Different SRC inhibitors have demonstrated potent anti-tumor activity in preclinical models, although they largely lack clinical efficacy as monotherapy in late-stage solid tumors, including head and neck squamous cell carcinomas (HNSCC). Adequate selection and stratification of patients who may respond to and benefit from anti-SRC therapies is therefore needed to guide clinical trials and treatment efficacy. This study investigates the prognostic significance of active SRC expression in a homogeneous cohort of 122 human papillomavirus (HPV)-negative, surgically treated HNSCC patients. Immunohistochemical evaluation of the active form of SRC by means of anti-SRC Clone 28 monoclonal antibody was specifically performed and subsequently correlated with clinical data. The expression of p-SRC (Tyr419), total SRC, and downstream SRC effectors was also analyzed. Our results uncovered striking differences in the prognostic relevance of SRC expression in HNSCC patients depending on the tumor site. Active SRC expression was found to significantly associate with advanced disease stages, presence of lymph node metastasis, and tumor recurrences in patients with laryngeal tumors, but not in the pharyngeal subgroup. Multivariate Cox analysis further revealed active SRC expression as an independent predictor of cancer-specific mortality in patients with laryngeal carcinomas. Concordantly, expression of p-SRC (Tyr419) and the SRC substrates focal adhesion kinase (FAK) and the Arf GTPase-activating protein ASAP1 also showed specific associations with poor prognosis in the larynx. These findings could have important implications in ongoing Src family kinase (SFK)-based clinical trials, as these new criteria could help to improve patient selection and develop biomarker-stratified trials.

TSPAN1: A Novel Protein Involved in Head and Neck Squamous Cell Carcinoma Chemoresistance

“…Moreover, TSPAN1 overexpression is associated to the development of an EMT program as consistently observed in mice tumors and HNSCC patient biopsies. Our findings support the notion that SRC activation may contribute to metastatic dissemination in HNSCC [25] and provide additional evidence extending the association of SRC activation with EMT to other HNSCC subtypes (i.e., laryngeal and pharyngeal carcinoma) beyond previous observations in nasopharyngeal carcinoma [56].…”

“…Staining was done at room temperature on an automatic staining workstation (Dako Autostainer Plus), using the Dako EnVision Flex + Visualization System (Dako Autostainer, Denmark) with the following antibodies: anti-TSPAN1 monoclonal antibody Clone HPA011909 (Sigma-Aldrich Química SL, Madrid, Spain) at 1:50 dilution, anti-E-Cadherin (BD Biosciences #610181, San Jose, CA, USA) at 1:4000 dilution and active SRC monoclonal antibody Clone 28 (Thermo Fisher Scientific #AHO0051) at 1:300 dilution. The SRC antibody, which detects the active protein, has been previously described [25]. Counterstaining with hematoxylin was the final step.…”

Exploring the Mechanism of Scutellaria baicalensis Georgi Efficacy against Oral Squamous Cell Carcinoma Based on Network Pharmacology and Molecular Docking Analysis

“…In this study, the data of the core target genes on median survival of OSCC patients suggested that PIK3R1, SRC, AKT1, MAPK3, and VEGFA are potential therapeutic targets of SBG; there was a correlation with the survival time of OSCC patients. PIK3R1, SRC, AKT1, MAPK3, and VEGFA are common therapeutic targets for OSCC closely related to the survival and prognosis of OSCC patients [31,53,65,66], which further supported the potential of SBG in the treatment of OSCC.…”

Anti‐growth and pro‐apoptotic effects of dasatinib on human oral cancer cells through multi‐targeted mechanisms

“…Src is a non‐receptor protein tyrosine kinase, 9,10 whose overexpression and hyperactivity are associated with tumour mass, metastasis, recurrence, angiogenesis and survival of patients with cancer 14‐16 . Of further note, studies have previously demonstrated that Src is overexpressed in OSCC, including tongue cancer, and there is a significant association of Src overexpression with progression, recurrence and prognosis of OSCC 11,17,18 . These findings strongly suggest Src inhibition as a targeted therapy for solid cancers, including tongue cancer.…”