Chemical Genetics Screen Identifies COPB2 Tool Compounds That Alters ER Stress Response and Induces RTK Dysregulation in Lung Cancer Cells |
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| Institution: | 1. Drug Discovery Program, Ontario Institute for Cancer Research, Ontario, Canada;2. Donnelly Centre, University of Toronto, Ontario, Canada;3. Biological Sciences, Sunnybrook Research Institute, Toronto, Ontario, Canada;4. Cell Biology, Department of Biology, Faculty of Science, Utrecht University, 3548CH Utrecht, the Netherlands;5. Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada;6. Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montreal, QC H3C 3J7, Canada;7. Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada;8. Department of Molecular Genetics, University of Toronto, Ontario, Canada;9. University of Toronto, Leslie Dan Faculty of Pharmacy, Toronto, Ontario, Canada;10. Department for Lung Diseases Jordanovac, Clinical Hospital Centre Zagreb, University of Zagreb, Zagreb, Croatia;11. Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada;12. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada;13. Department of Pharmacology and Toxicology, University of Toronto, Ontario, Canada;14. Department of Biochemistry, University of Toronto, Ontario, Canada;15. Mediterranean Institute for Life Sciences, Split, Croatia;16. School of Medicine, University of Split, Split, Croatia;1. European Paediatric Association/Union of National European Paediatric Societies and Associations (EPA/UNEPSA), Berlin, Germany;2. European Confederation of Primary Care Pediatricians (EPCP), Lyone, France;1. Department of Biochemistry, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;2. Department of Laboratory Medicine and Pathobiology, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada;1. Toronto General Hospital Research Institute, University Health Network, Toronto, ON M5G 1L7, Canada;2. Institute of Medical Research, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul 03181, South Korea;3. Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada;4. Multi-Organ Transplant Program, University Health Network, Toronto, ON M5G 1L7, Canada;5. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G1X5, Canada;6. Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada;7. Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada;8. Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 3E1, Canada;9. Departments of Biochemistry and Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada;10. Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada;11. Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada;12. Campbell Family Cancer Research Institute, University Health Network, Toronto, ON M5G 2C1, Canada;13. Division of Nephrology, Department of Medicine, Toronto General Hospital, University Health Network, Toronto, ON M5G 1L7, Canada;14. Division of Endocrinology and Metabolism, Department of Medicine, University Health Network and Sinai Health System, University of Toronto, Toronto, ON M5G 2C4, Canada |
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| Abstract: | Activating mutations in the epidermal growth factor receptor (EGFR) are common driver mutations in non-small cell lung cancer (NSCLC). First, second and third generation EGFR tyrosine kinase inhibitors (TKIs) are effective at inhibiting mutant EGFR NSCLC, however, acquired resistance is a major issue, leading to disease relapse. Here, we characterize a small molecule, EMI66, an analog of a small molecule which we previously identified to inhibit mutant EGFR signalling via a novel mechanism of action. We show that EMI66 attenuates receptor tyrosine kinase (RTK) expression and signalling and alters the electrophoretic mobility of Coatomer Protein Complex Beta 2 (COPB2) protein in mutant EGFR NSCLC cells. Moreover, we demonstrate that EMI66 can alter the subcellular localization of EGFR and COPB2 within the early secretory pathway. Furthermore, we find that COPB2 knockdown reduces the growth of mutant EGFR lung cancer cells, alters the post-translational processing of RTKs, and alters the endoplasmic reticulum (ER) stress response pathway. Lastly, we show that EMI66 treatment also alters the ER stress response pathway and inhibits the growth of mutant EGFR lung cancer cells and organoids. Our results demonstrate that targeting of COPB2 with EMI66 presents a viable approach to attenuate mutant EGFR signalling and growth in NSCLC. |
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