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

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Abstract
Certain tyrosine kinases are overactive in many cancers, and drugs that inhibit them, such as the leukaemia treatment imatinib, can be successful. But they don't work for all tyrosine kinase-driven cancers, and new work points to a possible reason why. The kinase HER2 is frequently overactive in breast cancers and signals through another family member, HER3. Sergina et al. find that when HER2 is partially blocked by kinase inhibitors, a feedback mechanism causes an increase of active HER3 at the plasma membrane where it continues to signal cancer cell proliferation. So more effective inhibitors that block HER2 completely, and reduce HER3 activity too, may be more effective cancer therapies. 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.