In silico identifying MET/FN1/TGFBI as molecular targets in drug-resistant head and neck cancer and preclinical repurposing sulfasalazine for enhanced therapeutic efficacy

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive cancer affecting over half a million people worldwide each year. Although recent FDA-approved treatments, like cetuximab, have shown promise, the five-year survival rate remains below 50 %. This underscores the need to identify molecular signatures predicting clinical outcomes and potential therapeutic targets. Notably, the alteration of tyrosine-protein kinase Met (c-Met), a hepatocyte growth factor (HGF) receptor, stimulates tumor growth and metastasis across various cancers. However, its role and clinical implications in HNSCC remain unexplored. In HNSCC, MET's downstream signaling, mediated by phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), is activated by fibronectin 1 (FN1), an extracellular matrix protein, fostering cancer progression. Additionally, FN1 and transforming growth factor-β (TGFB) are known to induce epithelial-mesenchymal transition in numerous cancers, leading to metastasis. Our computational analysis revealed significant upregulation of MET/FN1/TGFBI in HNSC at the mRNA level compared to normal samples. Given the immune system's pivotal role in HNSC progression, we analyzed the association of our target genes with immune infiltration. Our findings suggest a correlation between MET/FN1/TGFBI oncogenes and various stromal cells, highlighting their potential role in cancer recurrence and therapeutic resistance. We further explored the therapeutic potential of sulfasalazine, an anti-inflammatory drug. Molecular docking experiments revealed that sulfasalazine had a strong affinity for MET, FN1, and TGFBI, outperforming standard inhibitors in binding energy. These observations suggest sulfasalazine could be a promising MET/FN1/TGFBI gene signature inhibitor. Our study offers preclinical evidence supporting sulfasalazine as a standalone therapeutic agent and an adjunct to counteract cisplatin resistance in HNSC cells.