Abstract
Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. Identifying molecular mechanisms associated with acquired resistance to EGFR-TKIs such as erlotinib remains an unmet need and a therapeutic challenge. In this study, we employed an integrated multi-omics approach to delineate mechanisms associated with acquired resistance to erlotinib by carrying out whole exome sequencing, quantitative proteomic and phosphoproteomic profiling. We observed amplification of several genes including AXL kinase and transcription factor YAP1 resulting in protein overexpression. We also observed expression of constitutively active mutant MAP2K1 (p.K57E) in erlotinib resistant SCC-R cells. An integrated analysis of genomic, proteomic and phosphoproteomic data revealed alterations in MAPK pathway and its downstream targets in SCC-R cells. We demonstrate that erlotinib-resistant cells are sensitive to MAPK pathway inhibition. This study revealed multiple genetic, proteomic and phosphoproteomic alterations associated with erlotinib resistant SCC-R cells. Our data indicates that therapeutic targeting of MAPK pathway is an effective strategy for treating erlotinib-resistant HNSCC tumors.
Highlights
Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression
Erlotinibresistant (SCC-R) cells generated from HNSCC cell line UMSCC1 were used to investigate genetic and proteomic alterations associated with erlotinib resistance[10,11]
We evaluated the expression of Epithelial-mesenchymal transition (EMT) associated markers including E-cadherin, vimentin, snail and slug in SCC-R cells
Summary
Epidermal growth factor receptor (EGFR) targeted therapies have shown limited efficacy in head and neck squamous cell carcinoma (HNSCC) patients despite its overexpression. An integrated analysis of genomic, proteomic and phosphoproteomic data revealed alterations in MAPK pathway and its downstream targets in SCC-R cells. 12 Hr alterations associated with such resistance mechanisms remains unknown Exploring these mechanisms is essential to identify new therapeutic strategies that effectively target resistant tumors in HNSCC patients. Proteomic and phosphoproteomic approach can provide a broad framework to identify molecular alterations that drive altered signaling networks in erlotinib resistant HNSCC and enable identification of alternate therapeutic targets. Proteomic and phosphoproteomic approaches were employed to characterize activated signaling pathways in resistant cells Through this integrated multi-omics approach, we identified several molecular alterations in MAPK pathway downstream to EGFR that might govern erlotinib resistance in HNSCC by bypassing EGFR-mediated signaling
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