Targeting of EGFR by a combination of antibodies mediates unconventional EGFR trafficking and degradation
Autor: | Peter King, Clare E. Futter, Costin N. Antonescu, Mikkel W. Pedersen, Daniel Hochhauser, John A. Hartley, Michael Kragh, Sylwia Jones, Nicos Angelopoulos, Michael G. Sugiyama, Amandeep Bhamra, Silvia Surinova |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Ubiquitylation
Endosome lcsh:Medicine Antineoplastic Agents Receptors Cell Surface Membrane trafficking Endosomes Endocytosis Article Antibodies Targeted therapies Ubiquitin Cell surface receptor medicine Humans TSG101 Receptor lcsh:Science Transcription factor Cells Cultured Multidisciplinary Endosomal Sorting Complexes Required for Transport biology Chemistry Cell Membrane lcsh:R Growth factor signalling Antibodies Monoclonal Cancer Phosphoproteins medicine.disease DNA-Binding Proteins ErbB Receptors Protein Transport Head and Neck Neoplasms biology.protein Cancer research lcsh:Q Lysosomes Transcription Factors |
Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-19 (2020) Scientific Reports |
ISSN: | 2045-2322 |
DOI: | 10.1038/s41598-019-57153-9 |
Popis: | Antibody combinations targeting cell surface receptors are a new modality of cancer therapy. The trafficking and signalling mechanisms regulated by such therapeutics are not fully understood but could underlie differential tumour responses. We explored EGFR trafficking upon treatment with the antibody combination Sym004 which has shown promise clinically. Sym004 promoted EGFR endocytosis distinctly from EGF: it was asynchronous, not accompanied by canonical signalling events and involved EGFR clustering within detergent-insoluble plasma mebrane-associated tubules. Sym004 induced lysosomal degradation independently of EGFR ubiquitylation but dependent upon Hrs/Tsg101 that are required for the formation of intraluminal vesicles (ILVs) within late endosomes. We propose Sym004 cross-links EGFR physically triggering EGFR endocytosis and incorporation onto ILVs and so Sym004 sensitivity correlates with EGFR numbers available for binding, rather than specific signalling events. Consistently Sym004 efficacy and potentiation of cisplatin responses correlated with EGFR surface expression in head and neck cancer cells. These findings will have implications in understanding the mode of action of this new class of cancer therapeutics. |
Databáze: | OpenAIRE |
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