Abstract
SUMMARYSurface-targeting biotherapeutic agents have been successful in treating HER2-amplified cancers through immunostimulation or chemodelivery but have failed to produce effective inhibitors of constitutive HER2-HER3 signaling. We report an extensive structure-function analysis of this tumor driver, revealing complete uncoupling of intracellular signaling and tumorigenic function from regulation or constraints from their extracellular domains (ECDs). The canonical HER3 ECD conformational changes and exposure of the dimerization interface are nonessential, and the entire ECDs of HER2 and HER3 are redundant for tumorigenic signaling. Restricting the proximation of partner ECDs with bulk and steric clash through extremely disruptive receptor engineering leaves tumorigenic signaling unperturbed. This is likely due to considerable conformational flexibilities across the span of these receptor molecules and substantial undulations in the plane of the plasma membrane, none of which had been foreseen as impediments to targeting strategies. The massive overexpression of HER2 functionally and physically uncouples intracellular signaling from extracellular constraints.
Highlights
Aberrant activation of membrane-spanning receptor tyrosine kinases underlies the pathogenesis of many types of human cancers
We reconstructed the pathological state of massive human epidermal growth factor receptor 2 (HER2) overexpression and constitutive HER2-HER3 signaling in an experimental Chinese hamster ovary (CHO)-K1 cell expression system with high transfection efficiency and at levels that mimic HER2-amplified cancer cells (Figures S2A and S2B)
Normal physiological signaling is initiated by the interaction of HER3 with ligands, leading to conformational rearrangement of its extracellular domains (ECDs), exposing a dimerization interface that couples with a complementary interface on the ECD of HER2; the receptor proximation leads to dimerization of the intracellular kinase domains, and receptor phosphorylation ensues (Kovacs et al, 2015; Mitchell et al, 2018; Roskoski, 2014)
Summary
Aberrant activation of membrane-spanning receptor tyrosine kinases underlies the pathogenesis of many types of human cancers. The highly selective and favorable safety and pharmacokinetic profiles of ECD-targeting agents and well-established discovery platforms and manufacturing processes have made ECD-targeting agents a mainstay of cancer therapy. This approach has been challenging in the case of human epidermal growth factor receptor 2 (HER2)amplified cancers. Pertuzumab does interfere with ligand-induced HER2-HER3 signaling, consistent with its structure-based mechanism of action (Figure S1A; Agus et al, 2002; Sakai et al, 2007), but neither trastuzumab or pertuzumab are effective at disrupting constitutive HER2 signaling in HER2amplified cancer cells (Figure S1B). Investigational antibodies targeting the ECD of HER3 are effective at inhibiting ligand-driven physiologic HER2-HER3 signaling but are
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