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-amplifi...
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| Published in: | Breast cancer research : BCR Vol. 21; no. 1; pp. 43 - 17 |
|---|---|
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
| Format: | Journal Article |
| Language: | English |
| Published: |
London
BioMed Central
21.03.2019
BioMed Central Ltd Springer Nature B.V BMC |
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| ISSN: | 1465-542X, 1465-5411, 1465-542X |
| Online Access: | Get full text |
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| Abstract | 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. |
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| AbstractList | 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.BACKGROUNDThe 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.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.METHODSThrough 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.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.RESULTSWe 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.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.CONCLUSIONSThe 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. 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. 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. 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. 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. Abstract 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. 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. 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. 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. 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. 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. Keywords: ERBB2, Pertuzumab, Receptor tyrosine kinases, Breast cancer, Heterodimers 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. 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. |
| ArticleNumber | 43 |
| Audience | Academic |
| Author | Hastings, Jordan F. Watkins, D. Neil Saunders, Darren N. Nobis, Max Murphy, Kendelle J. Lim, Elgene Latham, Sharissa L. Williams, James T. Munoz, Amaya Garcia O’Donnell, Yolande E. I. Portman, Neil Miladinovic, Dushan Marriott, Gabriella R. Croucher, David R. Kennedy, Sean P. Kolch, Walter Cox, Thomas R. Shearer, Robert F. Cadell, Antonia L. Han, Jeremy Z. R. Timpson, Paul |
| Author_xml | – sequence: 1 givenname: Sean P. surname: Kennedy fullname: Kennedy, Sean P. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Systems Biology Ireland, University College Dublin – sequence: 2 givenname: Jeremy Z. R. surname: Han fullname: Han, Jeremy Z. R. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 3 givenname: Neil surname: Portman fullname: Portman, Neil organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St Vincent’s Hospital Clinical School, University of New South Wales – sequence: 4 givenname: Max surname: Nobis fullname: Nobis, Max organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 5 givenname: Jordan F. surname: Hastings fullname: Hastings, Jordan F. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 6 givenname: Kendelle J. surname: Murphy fullname: Murphy, Kendelle J. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 7 givenname: Sharissa L. surname: Latham fullname: Latham, Sharissa L. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 8 givenname: Antonia L. surname: Cadell fullname: Cadell, Antonia L. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 9 givenname: Dushan surname: Miladinovic fullname: Miladinovic, Dushan organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 10 givenname: Gabriella R. surname: Marriott fullname: Marriott, Gabriella R. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 11 givenname: Yolande E. I. surname: O’Donnell fullname: O’Donnell, Yolande E. I. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 12 givenname: Robert F. surname: Shearer fullname: Shearer, Robert F. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research – sequence: 13 givenname: James T. surname: Williams fullname: Williams, James T. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, School of Medicine, University of Notre Dame – sequence: 14 givenname: Amaya Garcia surname: Munoz fullname: Munoz, Amaya Garcia organization: Systems Biology Ireland, University College Dublin – sequence: 15 givenname: Thomas R. surname: Cox fullname: Cox, Thomas R. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St Vincent’s Hospital Clinical School, University of New South Wales – sequence: 16 givenname: D. Neil surname: Watkins fullname: Watkins, D. Neil organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St Vincent’s Hospital Clinical School, University of New South Wales – sequence: 17 givenname: Darren N. surname: Saunders fullname: Saunders, Darren N. organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, School of Medical Sciences, University of New South Wales – sequence: 18 givenname: Paul surname: Timpson fullname: Timpson, Paul organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St Vincent’s Hospital Clinical School, University of New South Wales – sequence: 19 givenname: Elgene surname: Lim fullname: Lim, Elgene organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St Vincent’s Hospital Clinical School, University of New South Wales – sequence: 20 givenname: Walter surname: Kolch fullname: Kolch, Walter organization: Systems Biology Ireland, University College Dublin, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, School of Medicine and Medical Science, University College Dublin – sequence: 21 givenname: David R. orcidid: 0000-0003-4965-8674 surname: Croucher fullname: Croucher, David R. email: d.croucher@garvan.org.au organization: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St Vincent’s Hospital Clinical School, University of New South Wales, School of Medicine and Medical Science, University College Dublin |
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| DOI | 10.1186/s13058-019-1127-y |
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| Keywords | Heterodimers Breast cancer Pertuzumab Receptor tyrosine kinases ERBB2 |
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The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it... The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates... Background The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it... Abstract Background The oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which... |
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| SubjectTerms | 1-Phosphatidylinositol 3-kinase Allosteric properties Animals Antibodies Antibodies, Monoclonal, Humanized - pharmacology Biomarkers Biomedical and Life Sciences Biomedicine Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer cells Cancer patients Cancer Research Cancer therapies Cell activation Cell culture Cell Line, Tumor Cell proliferation Chemotherapy Clinical trials Dimerization Disease Models, Animal Displays (Marketing) Dose-Response Relationship, Drug Drug Resistance, Neoplasm Drug therapy Enzyme inhibitors Epidermal growth factor Epidermal growth factor receptors ErbB-2 protein ErbB-3 protein ERBB2 Extracellular signal-regulated kinase Family relations Female Fluorescent Antibody Technique Heterodimers Humans Immunoglobulins Immunohistochemistry Immunotherapy Kinases Lapatinib Ligands Medical prognosis Metastasis Mice Monoclonal antibodies Oncology Patients Pertuzumab Phenols (Class of compounds) Phosphorylation Promiscuity Protein interaction Protein Kinase Inhibitors - pharmacology Protein Multimerization Protein-protein interactions Protein-tyrosine kinase receptors Receptor tyrosine kinases Receptor, ErbB-2 - antagonists & inhibitors Receptor, ErbB-2 - chemistry Receptor, ErbB-2 - metabolism Research Article Signal transduction Signal Transduction - drug effects Surgical Oncology Targeted cancer therapy Trastuzumab Trastuzumab - pharmacology Tumor cell lines Tyrosine Xenograft Model Antitumor Assays Xenografts |
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| Title | Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer |
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