TY - JOUR
T1 - 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
AU - Jain, Ankit P.
AU - Radhakrishnan, Aneesha
AU - Pinto, Sneha
AU - Patel, Krishna
AU - Kumar, Manish
AU - Nanjappa, Vishalakshi
AU - Raja, Remya
AU - Keshava Prasad, Thottethodi Subrahmanya
AU - Mathur, Premendu P.
AU - Sidransky, David
AU - Chatterjee, Aditi
AU - Gowda, Harsha
N1 - Funding Information:
R.R. is a recipient of fellowship from Science and Engineering Research Board, Department of Science and Technology (YSS/2014/000395), Government of India. H.G. is a recipient of NHMRC R.D. Wright Biomedical Career Development Fellowship. The results shown in the study are in part based upon data generated by the TCGA Research Network (https://www.cancer.gov/tcga). KinMap illustration reproduced courtesy of Cell Signaling Technology, Inc. (www.cellsignal.com).
Funding Information:
Institute of Bioinformatics is supported by Department of Biotechnology, Government of India Program Support on Neuroproteomics and infrastructure for proteomic data analysis (BT/01/COE/08/05). This work was supported by FAMRI-funded 072017_YCSA. K.P. is a recipient of Senior Research Fellowship from Council of Scientific and Industrial Research (CSIR), India. V.N. is a recipient of INSPIRE Faculty Award from the Department of Science and Technology, Government of India.
Publisher Copyright:
© Copyright 2021, Mary Ann Liebert, Inc., publishers 2021.
PY - 2021/9/1
Y1 - 2021/9/1
N2 - 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.
AB - 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.
KW - cancer research
KW - erlotinib resistance
KW - focal adhesion kinase
KW - head and neck cancer
KW - quantitative tyrosine phosphoproteomics
KW - tyrosine kinase inhibitors
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U2 - 10.1089/omi.2021.0057
DO - 10.1089/omi.2021.0057
M3 - Article
C2 - 34432535
AN - SCOPUS:85115156648
VL - 25
SP - 605
EP - 616
JO - OMICS A Journal of Integrative Biology
JF - OMICS A Journal of Integrative Biology
SN - 1536-2310
IS - 9
ER -