Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface
While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib,...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2018-05-01
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| Series: | eLife |
| Subjects: | |
| Online Access: | https://elifesciences.org/articles/32271 |
| _version_ | 1811181431975575552 |
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| author | Jeroen Claus Gargi Patel Flavia Autore Audrey Colomba Gregory Weitsman Tanya N Soliman Selene Roberts Laura C Zanetti-Domingues Michael Hirsch Francesca Collu Roger George Elena Ortiz-Zapater Paul R Barber Boris Vojnovic Yosef Yarden Marisa L Martin-Fernandez Angus Cameron Franca Fraternali Tony Ng Peter J Parker |
| author_facet | Jeroen Claus Gargi Patel Flavia Autore Audrey Colomba Gregory Weitsman Tanya N Soliman Selene Roberts Laura C Zanetti-Domingues Michael Hirsch Francesca Collu Roger George Elena Ortiz-Zapater Paul R Barber Boris Vojnovic Yosef Yarden Marisa L Martin-Fernandez Angus Cameron Franca Fraternali Tony Ng Peter J Parker |
| author_sort | Jeroen Claus |
| collection | DOAJ |
| description | While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation. By stabilising a particular HER2 conformer, lapatinib drives HER2-HER3 kinase domain heterocomplex formation. This dimer exists in a head-to-head orientation distinct from the canonical asymmetric active dimer. The associated clustering observed for these dimers predisposes to neuregulin responses, affording a proliferative outcome. Our findings provide mechanistic insights into the liabilities involved in targeting kinases with ATP-competitive inhibitors and highlight the complex role of protein conformation in acquired resistance. |
| first_indexed | 2024-04-11T09:16:40Z |
| format | Article |
| id | doaj.art-05bdc0b657ae488494f7ad21996d47c6 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:16:40Z |
| publishDate | 2018-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-05bdc0b657ae488494f7ad21996d47c62022-12-22T04:32:18ZengeLife Sciences Publications LtdeLife2050-084X2018-05-01710.7554/eLife.32271Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interfaceJeroen Claus0Gargi Patel1Flavia Autore2Audrey Colomba3Gregory Weitsman4Tanya N Soliman5https://orcid.org/0000-0002-4687-629XSelene Roberts6https://orcid.org/0000-0002-3732-0556Laura C Zanetti-Domingues7Michael Hirsch8Francesca Collu9Roger George10Elena Ortiz-Zapater11Paul R Barber12https://orcid.org/0000-0002-8595-1141Boris Vojnovic13Yosef Yarden14Marisa L Martin-Fernandez15Angus Cameron16Franca Fraternali17Tony Ng18Peter J Parker19https://orcid.org/0000-0002-6218-2933Protein Phosphorylation Laboratory, The Francis Crick Institute, London, United KingdomRichard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer Studies, Kings College London, London, United Kingdom; Sussex Cancer Centre, Brighton and Sussex University Hospitals, Brighton, United StatesRandall Division of Cell & Molecular Biophysics, Kings College London, London, United KingdomProtein Phosphorylation Laboratory, The Francis Crick Institute, London, United KingdomRichard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer Studies, Kings College London, London, United KingdomProtein Phosphorylation Laboratory, The Francis Crick Institute, London, United KingdomCentral Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United KingdomCentral Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United KingdomCentral Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United KingdomRandall Division of Cell & Molecular Biophysics, Kings College London, London, United KingdomThe Structural Biology Science Technology Platform, The Francis Crick Institute, London, United KingdomDepartment of Asthma, Allergy and Respiratory Science, King’s College London, Guy’s Hospital, London, United KingdomRandall Division of Cell & Molecular Biophysics, Kings College London, London, United Kingdom; UCL Cancer Institute, University College London, London, United KingdomRandall Division of Cell & Molecular Biophysics, Kings College London, London, United Kingdom; Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Oxford, United KingdomDepartment of Biological Regulation, Weizmann Institute of Science, Rehovot, IsraelCentral Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United KingdomProtein Phosphorylation Laboratory, The Francis Crick Institute, London, United Kingdom; Barts Cancer Institute, Queen Mary University of London, London, United KingdomRandall Division of Cell & Molecular Biophysics, Kings College London, London, United KingdomRichard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer Studies, Kings College London, London, United Kingdom; UCL Cancer Institute, University College London, London, United Kingdom; Breast Cancer Now Research Unit, Department of Research Oncology, Guy’s Hospital King’s College London School of Medicine, London, United KingdomProtein Phosphorylation Laboratory, The Francis Crick Institute, London, United Kingdom; School of Cancer and Pharmaceutical Sciences, King’s College London, Guy’s Campus, London, United KingdomWhile targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation. By stabilising a particular HER2 conformer, lapatinib drives HER2-HER3 kinase domain heterocomplex formation. This dimer exists in a head-to-head orientation distinct from the canonical asymmetric active dimer. The associated clustering observed for these dimers predisposes to neuregulin responses, affording a proliferative outcome. Our findings provide mechanistic insights into the liabilities involved in targeting kinases with ATP-competitive inhibitors and highlight the complex role of protein conformation in acquired resistance.https://elifesciences.org/articles/32271HER2HER3protein kinasepseudokinasekinase inhibitorslapatinib |
| spellingShingle | Jeroen Claus Gargi Patel Flavia Autore Audrey Colomba Gregory Weitsman Tanya N Soliman Selene Roberts Laura C Zanetti-Domingues Michael Hirsch Francesca Collu Roger George Elena Ortiz-Zapater Paul R Barber Boris Vojnovic Yosef Yarden Marisa L Martin-Fernandez Angus Cameron Franca Fraternali Tony Ng Peter J Parker Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface eLife HER2 HER3 protein kinase pseudokinase kinase inhibitors lapatinib |
| title | Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface |
| title_full | Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface |
| title_fullStr | Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface |
| title_full_unstemmed | Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface |
| title_short | Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface |
| title_sort | inhibitor induced her2 her3 heterodimerisation promotes proliferation through a novel dimer interface |
| topic | HER2 HER3 protein kinase pseudokinase kinase inhibitors lapatinib |
| url | https://elifesciences.org/articles/32271 |
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