Expression of eukaryotic initiationfactors (eIFs) in head and neck squamous cell carcinoma (HNSCC) and its potential therapeutic implications

The eukaryotic initiation factors regulate the rate-limiting phase of translation and when deregulated, may play a role in oncogenesis. We have previously shown that eIF2α is prognostically significant in HNSCC and may be pharmacologically targeted. The current study aims to characterize the expression of eIFs in HNSCC further, identify putative driver mutations and assess the potential of eIF2α in anticancer therapy.

Differential analysis of eIF mRNA-expression in HNSCC and normal tissue was performed with Oncomine, followed by survival analysis and correlation of mRNA data (TCGA, PanCancer Atlas) with clinical parameters, corrected by false discovery (FDR). DNA copy number alterations were correlated with eIF expression and adjusted for FDR to determine mutations driving the deregulation of eIF-expression. IHC was used to determine eIF2α protein abundance. HNSCC cell lines and patient-derived organoids (PDO) were treated with selective eIF2α-inhibitor.

Various eIFs are overexpressed in HNSCC, which often is a predictor of lower overall survival- notably, eIF2α has a higher predictive value than tumor staging. Several candidate driver mutations were revealed, most importantly, CDKN2A deletion. IHC confirmed higher eIF2α protein abundance in HNSCC samples. Pharmacological inhibition of eIF2α resulted in decreased cell viability and colony-forming in HNSCC cell lines. However, the effect differed with cell mutational characteristics; no significant decrease in viability of normal keratinocytes was seen. In PDO, targeting eIF2α lead to a dose-dependent decrease in viability.

eIF2α mRNA-expression is elevated and prognostically significant in HNSCC. CDKN2A deletion is one of potential drivers of its deregulation. eIF2α inhibition is a potential therapeutic strategy in HNSCC.

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Publication History

Article published online:
10 June 2020