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

研究成果: Article

5 引文 (Scopus)

摘要

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.

原文English
文章編號44021
期刊Scientific reports
7
DOIs
出版狀態Published - 2017 三月 14

指紋

Non-Small Cell Lung Carcinoma
Protein-Tyrosine Kinases
Pharmaceutical Preparations
Phosphotransferases
Phosphorylation
Mutation
Phosphoproteins
Proteome
Cell Survival
Proteins
gefitinib
Therapeutics

All Science Journal Classification (ASJC) codes

  • General

引用此文

Wang, Y. T., Pan, S. H., Tsai, C. F., Kuo, T. C., Hsu, Y. L., Yen, H. Y., ... Chen, Y. J. (2017). Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer. Scientific reports, 7, [44021]. https://doi.org/10.1038/srep44021
Wang, Yi Ting ; Pan, Szu Hua ; Tsai, Chia Feng ; Kuo, Ting Chun ; Hsu, Yuan Ling ; Yen, Hsin Yung ; Choong, Wai Kok ; Wu, Hsin Yi ; Liao, Yen Chen ; Hong, Tse-Ming ; Sung, Ting Yi ; Yang, Pan Chyr ; Chen, Yu Ju. / Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer. 於: Scientific reports. 2017 ; 卷 7.
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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.",
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Wang, YT, Pan, SH, Tsai, CF, Kuo, TC, Hsu, YL, Yen, HY, Choong, WK, Wu, HY, Liao, YC, Hong, T-M, Sung, TY, Yang, PC & Chen, YJ 2017, 'Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer', Scientific reports, 卷 7, 44021. https://doi.org/10.1038/srep44021

Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer. / Wang, Yi Ting; Pan, Szu Hua; Tsai, Chia Feng; Kuo, Ting Chun; Hsu, Yuan Ling; Yen, Hsin Yung; Choong, Wai Kok; Wu, Hsin Yi; Liao, Yen Chen; Hong, Tse-Ming; Sung, Ting Yi; Yang, Pan Chyr; Chen, Yu Ju.

於: Scientific reports, 卷 7, 44021, 14.03.2017.

研究成果: Article

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AU - Wang, Yi Ting

AU - Pan, Szu Hua

AU - Tsai, Chia Feng

AU - Kuo, Ting Chun

AU - Hsu, Yuan Ling

AU - Yen, Hsin Yung

AU - Choong, Wai Kok

AU - Wu, Hsin Yi

AU - Liao, Yen Chen

AU - Hong, Tse-Ming

AU - Sung, Ting Yi

AU - Yang, Pan Chyr

AU - Chen, Yu Ju

PY - 2017/3/14

Y1 - 2017/3/14

N2 - 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.

AB - 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.

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