Ras homolog family member A expression is associated with reduced cetuximab sensitivity in head and neck squamous...

ObjectivesGiven that intrinsic and acquired resistance to cetuximab substantially limits its therapeutic efficacy in head and neck squamous cell carcinoma, we sought to elucidate the role of Ras homolog family member A in mediating cetuximab resistance and delineate the mechanisms in both in vitro and in vivo models.MethodsOver 8 months, cetuximab-sensitive parental head and neck squamous cell carcinoma cells were exposed to progressively higher concentrations of cetuximab to develop a cetuximab-resistant head and neck squamous cell carcinoma cell line (HN31-R). Ribonucleic acid sequencing revealed significant upregulation of Ras homolog family member A and Rho-associated protein kinase in resistant cells compared with that in parental cells. The correlation between Ras homolog family member A overexpression and resistance to cetuximab was evaluated using Western blot analysis, immunofluorescence staining, and Cell Counting Kit-8 assays. Epigallocatechin-3-gallate was administered to Ras homolog family member A-overexpressing cells, and its effects on cetuximab sensitivity and tumor growth were evaluated in vitro and in a xenograft mouse model.ResultsElevated Ras homolog family member A expression is significantly associated with resistance to cetuximab. Ras homolog family member A knockdown restored cetuximab sensitivity and significantly reduced tumor growth in nude mice. Epigallocatechin-3-gallate treatment was associated with decreased Ras homolog family member A and Rho-associated protein kinase 2 expression and enhanced cetuximab sensitivity in both in vitro and xenograft models.ConclusionsRas homolog family member A may contribute to the development of cetuximab resistance and could be a candidate therapeutic target for future investigation aimed at improving treatment response in head and neck squamous cell carcinoma. The current findings suggest that modulation of the Ras homolog family member A-Rho-associated protein kinase axis is associated with cetuximab sensitivity in head and neck squamous cell carcinoma.