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

摘要: 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 kinase-driven new points to a possible reason why. The kinase HER2 is frequently breast cancers signals through another family member, HER3. Sergina et al. find when partially blocked by inhibitors, feedback mechanism causes an increase of active HER3 at plasma membrane where it continues signal cancer cell proliferation. So more effective inhibitors block completely, reduce activity too, may therapies. Oncogenic have proved promising targets development highly anticancer drugs. However, (TKIs) against human epidermal growth factor receptor (HER) show only limited HER2-driven despite inhibition (EGFR) vivo1,2,3,4,5,6,7,8. reasons this unclear. Signalling trans key feature multimember critically important phosphatidylinositol-3-OH (PI(3)K)/Akt pathway driven predominantly transphosphorylation kinase-inactive (refs 9, 10). Here we consequently PI(3)K/Akt signalling evade current HER-family TKIs vitro tumours vivo. This due compensatory shift phosphorylation–dephosphorylation equilibrium, increased expression driving phosphorylation reaction reduced phosphatase impeding dephosphorylation reaction. These changes Akt-mediated negative-feedback signalling. Although not direct target TKIs, substrate resistance undermines their efficacy has thus far gone undetected. experimental abrogation small interfering RNA knockdown restores potent pro-apoptotic otherwise cytostatic HER re-affirming oncogene-addicted nature therapeutic promise oncoprotein target. because buffered incomplete kinase, much or combination strategies required silence oncogenic effectively. biologic marker with which assess should rather than autophosphorylation.