How to Achieve Therapeutic Response in Erlotinib-Resistant Head and Neck Squamous Cell Carcinoma? New Insights from Stable Isotope Labeling with Amino Acids in Cell Culture-Based Quantitative Tyrosine Phosphoproteomics

OMICS. 2021 Sep;25(9):605-616. doi: 10.1089/omi.2021.0057. Epub 2021 Aug 24.


Resistance to cancer chemotherapy is a major global health burden. Epidermal growth factor receptor (EGFR) is a proven therapeutic target for multiple cancers of epithelial origin. Despite its overexpression in >90% of head and neck squamous cell carcinoma (HNSCC) patients, tyrosine kinase inhibitors such as erlotinib have shown a modest response in clinical trials. Cellular heterogeneity is thought to play an important role in HNSCC therapeutic resistance. Genomic alterations alone cannot explain all resistance mechanisms at play in a heterogeneous system. It is thus important to understand the biochemical mechanisms associated with drug resistance to determine potential strategies to achieve clinical response. We investigated tyrosine kinase signaling networks in erlotinib-resistant cells using quantitative tyrosine phosphoproteomics approach. We observed altered phosphorylation of proteins involved in cell adhesion and motility in erlotinib-resistant cells. Bioinformatics analysis revealed enrichment of pathways related to regulation of the actin cytoskeleton, extracellular matrix (ECM)-receptor interaction, and endothelial migration. Of importance, enrichment of the focal adhesion kinase (PTK2) signaling pathway downstream of EGFR was also observed in erlotinib-resistant cells. To the best of our knowledge, we present the first report of tyrosine phosphoproteome profiling in erlotinib-resistant HNSCC, with an eye to inform new ways to achieve clinical response. Our findings suggest that common signaling networks are at play in driving resistance to EGFR-targeted therapies in HNSCC and other cancers. Most notably, our data suggest that the PTK2 pathway genes may potentially play a significant role in determining clinical response to erlotinib in HNSCC tumors.

Keywords: cancer research; erlotinib resistance; focal adhesion kinase; head and neck cancer; quantitative tyrosine phosphoproteomics; tyrosine kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids
  • Carcinoma, Squamous Cell* / drug therapy
  • Carcinoma, Squamous Cell* / genetics
  • Cell Culture Techniques
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Erlotinib Hydrochloride / pharmacology
  • Head and Neck Neoplasms* / drug therapy
  • Head and Neck Neoplasms* / genetics
  • Humans
  • Isotope Labeling
  • Protein Kinase Inhibitors / pharmacology
  • Squamous Cell Carcinoma of Head and Neck / drug therapy
  • Squamous Cell Carcinoma of Head and Neck / genetics
  • Tyrosine


  • Amino Acids
  • Protein Kinase Inhibitors
  • Tyrosine
  • Erlotinib Hydrochloride