RRC ID 51772
Author Ellebaek S, Brix S, Grandal M, Lantto J, Horak ID, Kragh M, Poulsen TT.
Title Pan-HER-An antibody mixture targeting EGFR, HER2 and HER3 abrogates preformed and ligand-induced EGFR homo- and heterodimers.
Journal Int J Cancer
Abstract The human epidermal growth factor receptor (HER)-family is involved in development of many epithelial cancers. Therefore, HER-family members constitute important targets for anti-cancer therapeutics such as monoclonal antibodies (mAbs). A limitation to the success of single HER-targeting mAbs is development of acquired resistance through mechanisms such as alterted receptor dimerization patterns and dependencies. Pan-HER is a mixture of six mAbs simultaneously targeting epidermal growth factor receptor (EGFR), HER2 and HER3 with two mAbs against each receptor. Pan-HER has previously demonstrated broader efficacy than targeting single or dual receptor combinations also in resistant settings. In light of this broad efficacy, we decided to investigate the effect of Pan-HER compared with single HER-targeting with single and dual mAbs on HER-family cross-talk and dimerization focusing on EGFR. The effect of Pan-HER on cell proliferation and HER-family receptor degradation was superior to treatment with single mAbs targeting either single receptor, and similar to targeting a single receptor with two non-overlapping antibodies. Furthermore, changes in EGFR-dimerization patterns after treatment with Pan-HER were investigated by in situ proximity ligation assay and co-immunoprecipitation, demonstrating that Pan-HER and the EGFR-targeting mAb mixture efficiently down-regulate basal EGFR homo- and heterodimerization in two tested cell lines, whereas single mAbs had limited effects. Pan-HER and the EGFR-targeting mAb mixture also blocked EGF-binding and thereby ligand-induced changes in EGFR-dimerization levels. These results suggest that Pan-HER reduces the cellular capability to switch HER-dependency and dimerization pattern in response to treatment and thus hold promise for future clinical development of Pan-HER in resistant settings.
Volume 139(9)
Pages 2095-105
Published 2016-11-1
DOI 10.1002/ijc.30242
PMID 27342948
MeSH Antibodies, Monoclonal, Humanized / pharmacology* Cell Line, Tumor Cell Proliferation / drug effects Dimerization Drug Resistance, Neoplasm / drug effects ErbB Receptors / chemistry* ErbB Receptors / metabolism Gene Expression Regulation, Neoplastic Humans Neoplasms / chemistry Neoplasms / drug therapy Neoplasms / metabolism* Protein Binding / drug effects Receptor, ErbB-2 / chemistry* Receptor, ErbB-2 / metabolism Receptor, ErbB-3 / chemistry* Receptor, ErbB-3 / metabolism
IF 4.982
Times Cited 11
Resource
Human and Animal Cells PK-1(RCB1972)