Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer
Journal
Scientific Reports
Journal Volume
7
Journal Issue
1
Date Issued
2017
Author(s)
Chia-Feng Tsai
Hsu Y.-L.
Yen H.-Y.
Choong W.-K.
Wu H.-Y.
Liao Y.-C.
Hong T.-M.
Sung T.-Y.
Chen Y.-J.
Abstract
© 2017 The Author(s). Although EGFR tyrosine kinase inhibitors (TKIs) have demonstrated good efficacy in non-small-cell lung cancer (NSCLC) patients harboring EGFR mutations, most patients develop intrinsic and acquired resistance. We quantitatively profiled the phosphoproteome and proteome of drug-sensitive and drug-resistant NSCLC cells under gefitinib treatment. The construction of a dose-dependent responsive kinase-substrate network of 1548 phosphoproteins and 3834 proteins revealed CK2-centric modules as the dominant core network for the potential gefitinib resistance-associated proteins. CK2 knockdown decreased cell survival in gefitinib-resistant NSCLCs. Using motif analysis to identify the CK2 core sub-network, we verified that elevated phosphorylation level of a CK2 substrate, HMGA1 was a critical node contributing to EGFR-TKI resistance in NSCLC cell. Both HMGA1 knockdown or mutation of the CK2 phosphorylation site, S102, of HMGA1 reinforced the efficacy of gefitinib in resistant NSCLC cells through reactivation of the downstream signaling of EGFR. Our results delineate the TKI resistance-associated kinase-substrate network, suggesting a potential therapeutic strategy for overcoming TKI-induced resistance in NSCLC.
SDGs
Other Subjects
antineoplastic agent; epidermal growth factor receptor; gefitinib; high mobility group A1a protein; protein kinase inhibitor; quinazoline derivative; apoptosis; drug resistance; human; lung tumor; metabolism; non small cell lung cancer; phosphorylation; protein analysis; proteomics; tumor cell line; Antineoplastic Agents; Apoptosis; Carcinoma, Non-Small-Cell Lung; Cell Line, Tumor; Drug Resistance, Neoplasm; HMGA1a Protein; Humans; Lung Neoplasms; Phosphorylation; Protein Interaction Maps; Protein Kinase Inhibitors; Proteomics; Quinazolines; Receptor, Epidermal Growth Factor
Publisher
NATURE PUBLISHING GROUP
Type
journal article