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Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3

Nature volume 445, pages 437–441 (2007)Cite this article

Abstract

Oncogenic tyrosine kinases have proved to be promising targets for the development of highly effective anticancer drugs. However, tyrosine kinase inhibitors (TKIs) against the human epidermal growth factor receptor (HER) family show only limited activity against HER2-driven breast cancers, despite effective inhibition of epidermal growth factor receptor (EGFR) and HER2 in vivo1,2,3,4,5,6,7,8. The reasons for this are unclear. Signalling in trans is a key feature of this multimember family and the critically important phosphatidylinositol-3-OH kinase (PI(3)K)/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 (refs 9, 10). Here we show that HER3 and consequently PI(3)K/Akt signalling evade inhibition by current HER-family TKIs in vitro and in tumours in vivo. This is due to a compensatory shift in the HER3 phosphorylation–dephosphorylation equilibrium, driven by increased membrane HER3 expression driving the phosphorylation reaction and by reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt-mediated negative-feedback signalling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abrogation of HER3 resistance by small interfering RNA knockdown restores potent pro-apoptotic activity to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumours and the therapeutic promise of this oncoprotein target. However, because HER3 signalling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to silence oncogenic HER2 signalling effectively. The biologic marker with which to assess the efficacy of HER TKIs should be the transphosphorylation of HER3 rather than autophosphorylation.

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Figure 1: HER TKIs fail to induce sustained inhibition of HER3 signalling in HER2-driven breast cancer cells.
Figure 2: Forward shift in HER3 phosphorylation–dephosphorylation equilibrium following extended HER TKI treatment.
Figure 3: Mechanism of HER3 reactivation after extended HER TKI treatment.
Figure 4: Akt regulates HER3 signalling via negative feedback signalling.

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Acknowledgements

This work was supported by the Susan Komen Foundation (M.M.M.), the California Breast Cancer Research Program (M.M.M.), and an NIH grant (K.M.S.). We thank D. Stokoe and F. McCormick for review of the manuscript.

Author Contributions All authors contributed to the experiments in this work. The studies were conceived by M.M.M. with additional contributions from N.V.S. and K.M.S. The paper was written by N.V.S. and M.M.M.

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  1. Department of Medicine, University of California, San Francisco, 94143, USA

    Natalia V. Sergina, Megan Rausch, Donghui Wang, Byron Hann & Mark M. Moasser

  2. Department of Cellular and Molecular Pharmacology, University of California, San Francisco, 94143, USA

    Jimmy Blair & Kevan M. Shokat

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  1. Natalia V. Sergina
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Correspondence to Mark M. Moasser.

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This file contains supplementary figures 1-4, their legends, a detailed method and reagent section. (PDF 377 kb)

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Sergina, N., Rausch, M., Wang, D. et al. Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature 445, 437–441 (2007). https://doi.org/10.1038/nature05474

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