Background: Oral Squamous Cell Carcinoma (OSCC) is a major sub-type of oral cancer that shares 90% proportion of oral cavity cancers. It is declared as the sixth most frequent cancer among all cancer types throughout the world. Higher morbidity in Asian countries is reported due to frequent use of Smokeless Tobacco (SLT) products besides exposure to other risk factors. Hyperactivation of epidermal growth factor receptors is a molecular event in many solid tumors including oral cancer making them potential therapeutic targets. Objective: Current study was designed to explore the effect of varlitinib, a pan-HER inhibitor, on oral cancer cell line. We investigated key regulatory genes in downstream pathway in response to drug treatment. Furthermore, we also examined expression profile of these genes in malignant and healthy oral tissue. Method: Gene expression pattern in drug treated and untreated cancer cell line along with OSCC tumor samples (n=45) and adjacent normal tissues was studied using real time PCR. Results: In response to varlitinib treatment, significant suppression of oncogenes (IGF1R, MAPK1, SFN and CDK2) was observed. Interestingly, mRNA expression level of CDKN1A and Akt1 was found to be the opposite of what was expected. In case of malignant tissue, over expression of oncogenes (IGF1R, Akt1, MAPK1, SFN and CDK2) with simultaneous down expression of tumor suppressor genes (Tp53 and CDKN1A) was noted. STRING analysis indicated a strong association among differentially expressed genes suggesting their combined role in carcinogenesis. Conclusion: In summary, our results indicate that varlitinib can be considered as a potential therapeutic agent in oral cancer due to its antitumor potential.

Overexpression of epidermal growth factor receptor (EGFR) is commonly reported in epithelial malignancies such as oral squamous cell carcinoma. Inhibition of EGFR is, therefore, considered a potential therapeutic strategy. Among various anti-EGFR drugs, quinazoline-based tyrosine kinase inhibitors (TKIs) have gained increasing attention. Present study focused to investigate anti-EGFR potential of quinazoline-based compounds using in silico approach. Two widely used docking programs GOLD and AutoDock Vina were used for the study.Four drugs were docked on the X-ray crystallographic EGFR structure (1XKK). GOLD and AutoDock Vina produced results in terms of fitness score and binding affinity, respectively. GOLD prioritized varlitinib and AutoDock Vina preferred imatinib over other drugs. To reach the consensus from both software, all four drugs coupled with EGFR were studied rigorously. GOLD demonstrated varlitinib to be the best inhibitor with highest fitness score of 109, whereas AutoDock Vina revealed imatinib as the potent ligand with least binding energy of −10.9 kcal/mol. Most stable hydrogen bonds observed by GOLD and maximum number of hydrophobic contacts along with strong ionic interaction exhibited by varlitinib through both software have led us to conclude varlitinib as the most potent EGFR inhibitor in the studied group. K E Y W O R D Sbinding free energies, molecular target, oral epithelial malignancy, scoring function, tyrosine kinase inhibitors INTRODUCTIONCancer is considered as the leading cause of mortalities globally. 1,2 Among different types, oral squamous cell carcinoma (OSCC) is the leading cause of fatalities Abbreviations: EGFR, epidermal growth factor receptor; GOLD, genetic optimization for ligand docking; mAbs, monoclonal antibodies; OSCC, oral squamous cell carcinoma; TKIs, tyrosine kinase inhibitors

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Receptor-ligand complex mediated signaling significantly contributesin cellular activities such as growth, proliferation, differentiation, and survival. However, augmented expression of signal transducing receptors and ligands is the most frequent molecular event and major hallmark of oral carcinogenesis. Among these receptors, Epidermal Growth Factor Receptor (EGFR) with intracellular tyrosine kinase activity is the most frequently overexpressed molecule by Squamous epithelial cells of oral cavity. Aberrated EGFR mediated signaling has laid the foundation of targeted therapy thus providing rationale for the conducted study. We have selected EGFR pathway as targeted intracellular signaling cascade inOral squamous cell carcinoma (OSCC). Deactivating EGFR by blocking the binding sites is likely to result in prevention of intracellular downstream signaling. In this context, Tyrosine Kinase Inhibitors (TKIs) have come into play. Quinazolines (aromatic heterocyclic compounds) and their derivatives have shown promising clinical outcomes. Present study focused to investigate anti-EGFR potential of quinazoline derivative, varlitinib-a pan-EGFR inhibitor on oral squamous epithelial cell lines. We performed proteomic analyses to identify differential expression pattern of proteins in SCC-25 cells in response to varlitinib treatment. Identified proteins include Binding Immunoglobulin Protein (BiP), Heat Shock Protein 7C (HSP7C), Protein Disulfide Isomerase 1 A (PDIA1), Vimentin (VIME), Keratin type I Cytoskeletal 14 (K1C14), and β-Actin (ACTB). Among these, five proteinswere found to be downregulated upon varlitinib treatment whereas only Keratin type I Cytoskeletal 14 was upregulated. Differential expression of proteins and possible role of varlitinib as potential antitumor drug in oral carcinoma is discussed.