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FGA isoform as an indicator of targeted therapy for EGFR mutated lung adenocarcinoma

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Abstract

Epidermal growth factor receptor (EGFR) gene is frequently mutated in non-small cell lung cancer (NSCLC), which can be targeted by EGFR tyrosine kinase inhibitors (TKIs). It is hard, however, to monitor the performance of EGFR-TKI therapy dynamically. Therefore, therapeutic indicators are urgently needed. Novel antibody microarray, containing 41,472 antibodies, was used for comprehensive analyzing of serum samples from 9 normal subjects and 9 EGFR mutated lung adenocarcinoma patients at three EGFR-TKI treatment time points, including before treatment (Baseline), partial response (PR) during treatment, and disease progression (PD) after resistance. Through microarray data analysis, five candidate antibodies were screened out for confirmation in serum samples and the verified one was utilized for candidate protein identification through immunoprecipitation-mass spectrometry strategy. A novel protein, isoform 2 of fibrinogen alpha chain (FGA2), was revealed and verified in the discovery sample set. Its performance as therapy indicator was further evaluated in another pre-validation sample set (n = 60). Our data confirmed that serum FGA2 level was correlated with EGFR-TKI response (p < 0.05). The expression and secretion of FGA2 in hepatocytes were inhibited by EGFR-TKI, partially explaining the downregulation of FGA2 in serum. Our results demonstrate that FGA2 is an indicator of targeted therapy for EGFR mutated lung adenocarcinoma.

Key messages

  • Antibody microarray was coupled with mass spectrometry for proteomics research.

  • FGA2 was discovered as an indicator of EGFR-TKI targeted therapy.

  • FGA2’s expression/secretion in hepatocytes was dramatically inhibited by EGFR-TKI.

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Data availability

The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository (http://www.ebi.ac.uk/pride/) with the dataset identifier Project Accession: PXD010131.

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Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 21675110, 81972187, 31727801, 21305087, and 81302005), National Key Research and Development Program (Nos. 2017YFC1200204 and 2016YFC1303300), Projects of the Committee of Shanghai Science and Technology (Nos. 14DZ0501200, 15142200300, and 19ZR1449800), Clinical Research Project of Shanghai Municipal Public Health Bureau (No. 201840122), Advanced Appropriate Technology Promotion Project of Shanghai Municipal Public Health Bureau (No. 2019SY048), Research Project of Shanghai Municipal Cadre Health Bureau (No. 2017(12)), Doctoral Innovation Fund of Shanghai Jiao Tong University School of Medicine (No. BXJ201952), and Interdisciplinary Program of Shanghai Jiao Tong University (Nos. YG2014QN21, YG2015MS48, and YG2017MS80). H.X. is supported by the Recruitment Program of Global Youth Experts of China and National High-tech R&D Program of China (863 Program, No. 2014AA020545). X.M.N is supported by “Shanghai Young Physician Development Program” of Shanghai Municipal Public Health Bureau (No. 2012(105)).

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Author notes

  1. Zhi Shang, Xiaomin Niu and Kewei Zhang contributed equally to this work.

Authors and Affiliations

  1. State Key Laboratory of Microbial Metabolism, Joint International Research Laboratory of Metabolic & Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China

    Zhi Shang, Zhi Qiao, Sha Liu, Xiaoteng Jiang & Hua Xiao

  2. Department of Shanghai Lung Cancer Center, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030, China

    Xiaomin Niu & Shun Lu

  3. Department of Vascular and Endovascular Surgery, Henan Provincial People’s Hospital, People’s Hospital of Zhengzhou University, People’s Hospital of Henan University, Zhengzhou, 450003, Henan, China

    Kewei Zhang

  4. Department of Instrument Science and Engineering, School of Electronic Information and Electrical Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China

    Chengxi Cao

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  1. Zhi Shang
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Contributions

H.X. and X.M.N. contributed to the study design. Z.S., X.M.N., and K.W.Z. contributed to cell culture and sample collection. Z.S. conducted the experiments and collected the data. X.M.N. and K.W.Z. collected the clinical data. Z.S., X.M.N., K.W.Z., Z.Q., S.L., X.T.J., C.X.C., S.L., and H.X. contributed to the data analysis. The manuscript was written by Z.S., X.M.N., K.W.Z., and H.X. All the authors reviewed the manuscript. All aspects of the study were supervised by H.X. and S.L.

Corresponding authors

Correspondence to Shun Lu or Hua Xiao.

Ethics declarations

The current study adhered to the tenets of the Declaration of Helsinki and was performed after approval by the Institutional Review Board (IRB) of Shanghai Chest Hospital (IRB#KS1753 approved by Shanghai Chest Hospital Ethics Committee). All patients signed the IRB-approved written informed consents and were further enrolled for this study, allowing for the collection and analysis of blood samples. Serum samples from healthy control subjects were collected randomly from physical examination center of the Henan Provincial People’s Hospital (IRB#M15017 approved by Bio-X Ethics Committee of Shanghai Jiao Tong University). All control subjects provided written informed consents and had no history of any cancer.

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The authors declare that they have no competing interests.

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Shang, Z., Niu, X., Zhang, K. et al. FGA isoform as an indicator of targeted therapy for EGFR mutated lung adenocarcinoma. J Mol Med 97, 1657–1668 (2019). https://doi.org/10.1007/s00109-019-01848-z

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  • DOI: https://doi.org/10.1007/s00109-019-01848-z

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