title: Targeting HER2(+) breast cancer: the TBK1/IKKε axis.
abstract: HER2(+) breast cancer (BC) is a highly aggressive subtype, affecting ~20% of BC patients. Current treatments include adjuvant or neoadjuvant chemotherapy plus anti-HER2 agents such as trastuzumab, a monoclonal antibody directed against HER2. Despite improvement in disease free survival, most patients eventually succumb to metastatic disease, which is largely incurable. Consequently, there is an urgent need to identify novel drugs that can efficiently kill HER2(+) BC and/or potentiate the effect of existing anti-HER2 therapies. We performed a lenti-viral shRNA kinome screen on non-adherent mouse Her2/Neu tumorspheres and identified TBK1, a non-canonical IκB kinase (IKK), as the most potent target [1]. TBK1 knock-down, or treatment with TBK1-II, a drug that efficiently inhibits TBK1 and its close relative IKKε (IKBKE), suppressed growth of human HER2(+) BC cells and induced cellular senescence. Senescence was associated with inhibition of phosphorylated/active p65-NFkB and induction of the cell cycle inhibitor, p16(ink4a). In addition, TBK1-II cooperated with lapatinib, a EGFR/HER2 inhibitor, to accelerate apoptosis in vitro and suppress tumor growth in a xenograft model of HER2(+) BC. Thus, TBK1/IKKε inhibitors may improve treatment of HER2(+) BC in cooperation with anti-HER2 therapy.
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
authors.forename: Jeff C
authors.initials: JC
authors.lastname: Liu
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
authors.forename: Philip E D
authors.initials: PE
authors.lastname: Chung
authors.affiliation: Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Department of Molecular Genetics, University of Toronto.
authors.forename: Sean E
authors.initials: SE
authors.lastname: Egan
authors.affiliation: Division of Advanced Diagnostics, Toronto General Research Institute - University Health Network, Toronto, Ontario, Canada.
authors.forename: Eldad
authors.initials: E
authors.lastname: Zacksenhaus
keywords: Breast cancer; HER2; IKKε; TBK1; therapy