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Elife. 2018 May 1;7. pii: e32271. doi: 10.7554/eLife.32271.

Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface.

Author information

1
Protein Phosphorylation Laboratory, The Francis Crick Institute, London, United Kingdom.
2
Richard Dimbleby Department of Cancer Research, Randall Division and Division of Cancer Studies, Kings College London, London, United Kingdom.
3
Sussex Cancer Centre, Brighton and Sussex University Hospitals, Brighton, United States.
4
Randall Division of Cell & Molecular Biophysics, Kings College London, London, United Kingdom.
5
Central Laser Facility, Research Complex at Harwell, Science and Technology Facilities Council, Rutherford Appleton Laboratory, Didcot, United Kingdom.
6
The Structural Biology Science Technology Platform, The Francis Crick Institute, London, United Kingdom.
7
Department of Asthma, Allergy and Respiratory Science, King's College London, Guy's Hospital, London, United Kingdom.
8
UCL Cancer Institute, University College London, London, United Kingdom.
9
Department of Oncology, Cancer Research UK and Medical Research Council Oxford Institute for Radiation Oncology, Oxford, United Kingdom.
10
Department of Biological Regulation, Weizmann Institute of Science, Rehovot, Israel.
11
Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
12
Breast Cancer Now Research Unit, Department of Research Oncology, Guy's Hospital King's College London School of Medicine, London, United Kingdom.
13
School of Cancer and Pharmaceutical Sciences, King's College London, Guy's Campus, London, United Kingdom.
#
Contributed equally

Abstract

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.

KEYWORDS:

HER2; HER3; cancer biology; cell biology; human; kinase inhibitors; lapatinib; protein kinase; pseudokinase

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