Open AccessHow 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
Author(s) -
Ankit Jain,
Aneesha Radhakrishnan,
Sneha M. Pinto,
Krishna Patel,
Manish Kumar,
Vishalakshi Nanjappa,
Remya Raja,
Thottethodi Subrahmanya Keshava Prasad,
P. B. Mathur,
David Sidransky,
Aditi Chatterjee,
Harsha Gowda
Publication year - 2021
Publication title -
omics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.811
H-Index - 58
eISSN - 1557-8100
pISSN - 1536-2310
DOI - 10.1089/omi.2021.0057
Subject(s) - erlotinib , head and neck squamous cell carcinoma , stable isotope labeling by amino acids in cell culture , phosphoproteomics , cancer research , biology , epidermal growth factor receptor , receptor tyrosine kinase , tyrosine kinase , ptk2 , signal transduction , erlotinib hydrochloride , cancer , kinase , microbiology and biotechnology , head and neck cancer , proteomics , protein kinase a , genetics , gene , protein kinase c , mitogen activated protein kinase kinase , protein phosphorylation
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.