Abstract
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.
Highlights
Antibody combinations targeting cell surface receptors are a new modality of cancer therapy
The Epidermal Growth Factor Receptor (EGFR)-targeting monoclonal antibodies cetuximab and panitumumab have been widely used for treatment of KRAS wild-type colorectal cancer, whereas the HER2-targeting antibody trastuzumab has been successful in HER2-amplified breast cancers[1,2]
The Sym004-EGFR clusters were subsequently targeted for lysosomal degradation independently of EGFR ubiquitylation, but dependent upon the functionality of the ESCRT machinery required for the formation of intraluminal vesicles (ILVs) within late endosomes
Summary
Antibody combinations targeting cell surface receptors are a new modality of cancer therapy. We propose that cross-linking of multiple EGFR molecules within detergent-insoluble plasma membrane clusters physically triggers unconventional EGFR trafficking, i.e. prolonged and asynchronous EGFR endocytosis and degradation, without the requirement for the canonical signalling events, and so Sym004-mediated EGFR degradation correlates primarily with the accessibility of EGFR molecules at the plasma membrane/lower proportion of endosomal EGFR unavailable for Sym[004] binding In favour of this model we showed that Sym[004] treatment was much more potent in head and neck cancer (HNC) cells with higher expression of cell surfaceEGFR, and Sym[004] potentiated response to chemotherapy in these cells
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