1. Quantitative proteomics analysis identifies MUC1 as an effect sensor of EGFR inhibition
- Author
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Martin Pool, Elisabeth G.E. de Vries, Fabrizia Fusetti, Harry J.M. Groen, Esméé Joosten, Suzanne van Cooten, Douwe F. Samplonius, Rudolf S N Fehrmann, Marcel A. T. M. van Vugt, Marieke Everts, H. Rudolf de Boer, Wijnand Helfrich, Targeted Gynaecologic Oncology (TARGON), Translational Immunology Groningen (TRIGR), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), and Enzymology
- Subjects
Proteomics ,STAT3 Transcription Factor ,0301 basic medicine ,EXPRESSION ,Cancer Research ,PROGNOSIS ,Quantitative proteomics ,Apoptosis ,UP-REGULATION ,GEFITINIB ,Erlotinib Hydrochloride ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Gefitinib ,LUNG-CANCER ,Downregulation and upregulation ,Carcinoma, Non-Small-Cell Lung ,Cell Line, Tumor ,Genetics ,medicine ,Animals ,Humans ,Epidermal growth factor receptor ,Lung cancer ,skin and connective tissue diseases ,MET AMPLIFICATION ,Protein Kinase Inhibitors ,Molecular Biology ,neoplasms ,DRUG DEVELOPMENT ,Cell Proliferation ,biology ,Mucin-1 ,Cancer ,medicine.disease ,Xenograft Model Antitumor Assays ,FAMILY ,ErbB Receptors ,030104 developmental biology ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Erlotinib ,STAT3 ACTIVATION ,RESISTANCE ,medicine.drug ,Blood sampling - Abstract
Tumor responses to cancer therapeutics are generally monitored every 2-3 months based on changes in tumor size. Dynamic biomarkers that reflect effective engagement of targeted therapeutics to the targeted pathway, so-called "effect sensors", would fulfill a need for non-invasive, drug-specific indicators of early treatment effect. Using a proteomics approach to identify effect sensors, we demonstrated MUC1 upregulation in response to epidermal growth factor receptor (EGFR)targeting treatments in breast and lung cancer models. To achieve this, using semi-quantitative mass spectrometry, we found MUC1 to be significantly and durably upregulated in response to erlotinib, an EGFR-targeting treatment. MUC1 upregulation was regulated transcriptionally, involving PI3K-signaling and STAT3. We validated these results in erlotinib-sensitive human breast and non-small lung cancer cell lines. Importantly, erlotinib treatment of mice bearing SUM149 xenografts resulted in increased MUC1 shedding into plasma. Analysis of MUC1 using serial blood sampling may therefore be a new, relatively non-invasive tool to monitor early and drug-specific effects of EGFR-targeting therapeutics.
- Published
- 2019