@article{db56f8e46f564e7b8178162f99aacfb9,
title = "Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface",
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.",
author = "Jeroen Claus and Gargi Patel and Flavia Autore and Audrey Colomba and Gregory Weitsman and Soliman, \{Tanya N.\} and Selene Roberts and Zanetti-Domingues, \{Laura C.\} and Michael Hirsch and Francesca Collu and Roger George and Elena Ortiz-Zapater and Barber, \{Paul R.\} and Boris Vojnovic and Yosef Yarden and Martin-Fernandez, \{Marisa L.\} and Angus Cameron and Franca Fraternali and Tony Ng and Parker, \{Peter J.\}",
note = "We would like to thank Mark Lemmon for kindly providing HER3 baculoviral constructs. We wish to thank Melanie Keppler for making some of the HER2 mutants used in the experiments; as well as Luis Fernandes for some of the initial HER2-HER3 modelling work. We thank Gilbert Fruwirth for the fluorescent labelling of antibodies for the FRET-FLIM experiments. We thank the Flow Cytometry core facility at the Francis Crick Institute for carrying out the flow cytometry experiments and analysis. This work was supported by Cancer Research UK (C1519/A10331, C133/A1812, and C1519/ A6906), the Biotechnology and Biological Sciences Research Council (BB/G007160/1 and BB/ H018409/1), Dimbleby Cancer Care, KCL-UCL Comprehensive Cancer Imaging Centre (supported by Cancer Research UK/EPSRC) and in association with the MRC and DoH, The Medical Research Council (MR/L01257X/1 and MR/K015591/1), EU FP7 IMAGINT (EC GRANT: 259881), and the Swiss National Science Foundation.",
year = "2018",
month = may,
day = "1",
doi = "10.7554/eLife.32271",
language = "الإنجليزيّة",
volume = "7",
journal = "eLife",
issn = "2050-084X",
publisher = "eLife Sciences Publications Ltd",
}