TY - JOUR
T1 - Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface
AU - Claus, Jeroen
AU - Patel, Gargi
AU - Autore, Flavia
AU - Colomba, Audrey
AU - Weitsman, Gregory
AU - Soliman, Tanya N.
AU - Roberts, Selene
AU - Zanetti-Domingues, Laura C.
AU - Hirsch, Michael
AU - Collu, Francesca
AU - George, Roger
AU - Ortiz-Zapater, Elena
AU - Barber, Paul R.
AU - Vojnovic, Boris
AU - Yarden, Yosef
AU - Martin-Fernandez, Marisa L.
AU - Cameron, Angus
AU - Fraternali, Franca
AU - Ng, Tony
AU - Parker, Peter J.
N1 - 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.
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
U2 - https://doi.org/10.7554/eLife.32271
DO - https://doi.org/10.7554/eLife.32271
M3 - مقالة
C2 - 29712619
SN - 2050-084X
VL - 7
JO - eLife
JF - eLife
M1 - 32271
ER -