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.
Highlights
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common cancer worldwide
SRC belongs to the highly conserved family of non-receptor protein tyrosine kinases known as the Src family kinases (SFKs) that includes SRC, BLK, FGR, FRK, FYN, HCK, LCK, LYN, YES, and YRK [3,4]
Surgical tissue specimens were collected from 122 patients with laryngeal or hypopharyngeal squamous cell carcinoma surgically treated at the Hospital Universitario Central de Asturias (HUCA) between 1996 and 2005, in accordance with approved Institutional Review Board guidelines
Summary
Head and neck squamous cell carcinoma (HNSCC) represents the sixth most common cancer worldwide. The latest advancements in cancer diagnosis and treatment have led to only modest improvements of survival rates for HNSCC patients [1]. It has become clear by omics studies that. HNSCC is a highly complex and heterogeneous disease [2], involving multiple different genetic and molecular alterations that hamper our ability to accurately predict aggressive tumor behavior. The identification of novel markers capable of distinguishing the biological behavior of tumors could certainly contribute to improve predictability beyond the current clinicopathological markers. Each family member has shown a different expression pattern and tissue distribution
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