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

Abstract

Oncogenic tyrosine kinases have proven to be promising targets for the development of highly effective anticancer drugs. However HER family tyrosine kinase inhibitors (TKIs) show only limited activity against HER2-driven cancers despite effective inhibition of EGFR and HER2 in vivo 1–8. The reasons for this are unclear. Signaling in trans is a key feature of this multimember family and the critically important PI3K/Akt pathway is driven predominantly through transphosphorylation of the kinase-inactive HER3 9,10. We report that HER3 and consequently PI3K/Akt signaling evade inhibition by current HER family TKIs in vitro and in tumors in vivo. This is due to a compensatory shift in HER3 phosphorylation-dephosphorylation equilibrium driven by increased membrane HER3 expression driving the phosphorylation reaction and reduced HER3 phosphatase activity impeding the dephosphorylation reaction. These compensatory changes are driven by Akt mediated negative feedback signaling. Although HER3 is not a direct target of TKIs, HER3 substrate resistance undermines their efficacy and has thus far gone undetected. The experimental abbrogation of HER3 resistance by siRNA knockdown restores potent pro-apoptotic effects to otherwise cytostatic HER TKIs, re-affirming the oncogene-addicted nature of HER2-driven tumors and the therapeutic promise of this oncoprotein target. However, since HER3 signaling is buffered against an incomplete inhibition of HER2 kinase, much more potent TKIs or combination strategies are required to effectively silence oncogenic HER2 signaling. The biologic marker to guide HER TKIs should be the transphosphorylation of HER3.

Targeting the function of the HER2 oncogene in human cancer therapeutics

“…Tumor biodistribution does not seem to be a limiting step since, at least with regards to gefitinib, tumor and tissue concentrations have been measured and are much higher than serum concentrations and well above concentrations that fully suppress EGFR and HER2 signaling in cell-culture models (McKillop et al, 2005). (Sergina et al, 2007). This is due to Akt-driven negative feebdack signaling, which restores HER3-signaling activity despite significant suppression of HER2 kinase function, and thereby maintaining downstream Aktsignaling and numerous Akt-driven pathways important for tumor survival (Sergina et al, 2007).…”

“…(Sergina et al, 2007). This is due to Akt-driven negative feebdack signaling, which restores HER3-signaling activity despite significant suppression of HER2 kinase function, and thereby maintaining downstream Aktsignaling and numerous Akt-driven pathways important for tumor survival (Sergina et al, 2007). This feedback loop essentially buffers HER3 signaling against the incomplete loss of HER2 kinase function and underscores the tumor cells critical need to maintain Aktsignaling and numerous Akt-driven pathways important for tumor survival.…”

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity

“…Ligand binding and/or receptor overexpression induces homo-or heterodimerization of HER receptors, transphosphorylation of the kinase domains and subsequent activation of downstream signaling (Tzahar et al, 1996;Yarden and Sliwkowski, 2001;Citri and Yarden, 2006;Sergina et al, 2007). Overexpression/amplification of HER2 is seen in approximately 25-30% of human breast cancers and is associated with a more malignant phenotype and a worse prognosis (Slamon et al, 1987(Slamon et al, , 1989.…”

Phosphorylation of the ErbB3 binding protein Ebp1 by p21-activated kinase 1 in breast cancer cells

“…The ErbB2/ErbB3 receptor pair forms the most potent mitogenic receptor complex in vitro (Pinkas-Kramarski et al, 1996b) and is key to the proliferation of human breast cancer cells (Holbro et al, 2003a). The importance of ErbB3 expression in breast cancer has been recently highlighted by the demonstration that continued oncogenic signalling through ErbB3 in human breast cancer cell lines results in the failure of gefitinib to completely inhibit the kinase activity of ErbB2 (Sergina et al, 2007).…”