title: Phosphoproteomics Reveals HMGA1, a CK2 Substrate, as a Drug-Resistant Target in Non-Small Cell Lung Cancer.
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.
authors.affiliation: Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Institute of Biochemical Sciences, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Wang
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan.|Genome and Systems Biology Degree Program, National Taiwan University and Academia Sinica, Taipei, 11529, Taiwan.|Ph. D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Szu-Hua
authors.initials: SH
authors.lastname: Pan
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Chia-Feng
authors.initials: CF
authors.lastname: Tsai
authors.affiliation: Ph. D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Ting-Chun
authors.initials: TC
authors.lastname: Kuo
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, College of Medicine, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Yuan-Ling
authors.initials: YL
authors.lastname: Hsu
authors.affiliation: Genomics Research Center, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Hsin-Yung
authors.initials: HY
authors.lastname: Yen
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Wai-Kok
authors.initials: WK
authors.lastname: Choong
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Wu
authors.affiliation: Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Yen-Chen
authors.initials: YC
authors.lastname: Liao
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, 70101, Taiwan.
authors.forename: Tse-Ming
authors.initials: TM
authors.lastname: Hong
authors.affiliation: Institute of Information Science, Academia Sinica, Taipei, 11529, Taiwan.
authors.forename: Ting-Yi
authors.initials: TY
authors.lastname: Sung
authors.affiliation: Ph. D. Program in Translational Medicine, National Taiwan University and Academia Sinica, Taipei, 11529, Taiwan.|Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University Medical College, Taipei, 10617, Taiwan.|Institute of Biomedical Science, Academia Sincia, Taipei, 11529, Taiwan.
authors.forename: Pan-Chyr
authors.initials: PC
authors.lastname: Yang
authors.affiliation: Chemical Biology and Molecular Biophysics Program, Taiwan International Graduate Program, Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Institute of Chemistry, Academia Sinica, Taipei, 11529, Taiwan.|Department of Chemistry, National Taiwan University, Taipei, 10617, Taiwan.
authors.forename: Yu-Ju
authors.initials: YJ
authors.lastname: Chen
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000378:metabolism; D000077156:Gefitinib; D025741:HMGA1a Protein / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D010766:Phosphorylation; D060066:Protein Interaction Maps; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040901:Proteomics; D011799:Quinazolines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D025741:HMGA1a Protein; D066246:ErbB Receptors; D000077156:Gefitinib