Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer

Yi Ting Wang, Szu Hua Pan, Chia Feng Tsai, Ting Chun Kuo, Yuan Ling Hsu, Hsin Yung Yen, Wai Kok Choong, Hsin Yi Wu, Yen Chen Liao, Tse Ming Hong, Ting Yi Sung, Pan Chyr Yang, Yu Ju Chen

Research output: Contribution to journalArticlepeer-review

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article number44021
JournalScientific reports
Volume7
DOIs
Publication statusPublished - 2017 Mar 14

All Science Journal Classification (ASJC) codes

  • General

Fingerprint

Dive into the research topics of 'Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer'. Together they form a unique fingerprint.

Cite this