Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer.
Background: The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplif...
| Publicado en: | Breast Cancer Research Vol. 21; no. 1 |
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| Autores principales: | , , , , , , , , , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
BioMed Central
3/21/2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=135468055&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 135468055 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 14655411 8UYJ jtl: Breast Cancer Research issn: 14655411 maglogo: N pubinfo: dt: 3/21/2019 vid: 21 iid: 1 pid: 24147 pub: BioMed Central artinfo: ui: 135468055 135468055 NLM30898150 135468055 10.1186/s13058-019-1127-y NLM30898150 135468055 ppct: 1 formats: fmt: – @attributes: type: T – @attributes: type: P tig: atl: Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer. aug: au: Kennedy, Sean P. Han, Jeremy Z. R. Portman, Neil Nobis, Max Hastings, Jordan F. Murphy, Kendelle J. Latham, Sharissa L. Cadell, Antonia L. Miladinovic, Dushan Marriott, Gabriella R. O'Donnell, Yolande E. I. Shearer, Robert F. Williams, James T. Munoz, Amaya Garcia Cox, Thomas R. Watkins, D. Neil Saunders, Darren N. Timpson, Paul Lim, Elgene Kolch, Walter affil: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 370 Victoria St, Darlinghurst, 2010, Sydney, NSW, Australia sug: subj: Receptors, Cell Surface Drug Resistance, Neoplasm Breast Neoplasms Metabolism Receptors, Cell Surface Metabolism Protein Kinase Inhibitors Pharmacodynamics Biochemical Phenomena Animal Studies Breast Neoplasms Pathology Antibodies, Monoclonal Pharmacodynamics Breast Neoplasms Drug Therapy Phosphorylation Fluorescent Antibody Technique Dose-Response Relationship, Drug Female Cell Line, Tumor Human Immunohistochemistry Models, Biological Mice Receptors, Cell Surface Antagonists and Inhibitors Signal Transduction Drug Effects Validation Studies Comparative Studies Evaluation Research Multicenter Studies Female ab: Background: The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.Methods: Through a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model.Results: We now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models.Conclusions: The interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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