title: Engineered bivalent ligands to bias ErbB receptor-mediated signaling and phenotypes.
abstract: The ErbB receptor family is dysregulated in many cancers, and its therapeutic manipulation by targeted antibodies and kinase inhibitors has resulted in effective chemotherapies. However, many malignancies remain refractory to current interventions. We describe a new approach that directs ErbB receptor interactions, resulting in biased signaling and phenotypes. Due to known receptor-ligand affinities and the necessity of ErbB receptors to dimerize to signal, bivalent ligands, formed by the synthetic linkage of two neuregulin-1β (NRG) moieties, two epidermal growth factor (EGF) moieties, or an EGF and a NRG moiety, can potentially drive homotypic receptor interactions and diminish formation of HER2-containing heterodimers, which are implicated in many malignancies and are a prevalent outcome of stimulation by native, monovalent EGF, or NRG. We demonstrate the therapeutic potential of this approach by showing that bivalent NRG (NN) can bias signaling in HER3-expressing cancer cells, resulting in some cases in decreased migration, inhibited proliferation, and increased apoptosis, whereas native NRG stimulation increased the malignant potential of the same cells. Hence, this new approach may have therapeutic relevance in ovarian, breast, lung, and other cancers in which HER3 has been implicated.
authors.affiliation: From the Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jay
authors.forename: Elma
authors.initials: E
authors.lastname: Kurtagic
authors.forename: Luis M
authors.initials: LM
authors.lastname: Alvarez
authors.forename: Seymour
authors.initials: S
authors.lastname: de Picciotto
authors.forename: Edgar
authors.initials: E
authors.lastname: Sanchez
authors.forename: Jessica F
authors.initials: JF
authors.lastname: Hawkins
authors.forename: Robin N
authors.initials: RN
authors.lastname: Prince
authors.forename: Yadir
authors.initials: Y
authors.lastname: Guerrero
authors.forename: Carolyn L
authors.initials: CL
authors.lastname: Treasure
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: Linda G
authors.initials: LG
authors.lastname: Griffith
mesh_terms: D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000378:metabolism / Q000473:pathology; D020890:Neuregulin-1 / Q000378:metabolism; D010641:Phenotype; D015202:Protein Engineering; D020893:Receptor, ErbB-3 / Q000378:metabolism*; D015398:Signal Transduction; D020349:Surface Plasmon Resonance
chemical_list: D008024:Ligands; D020890:Neuregulin-1; C117467:neuregulin beta; D020893:Receptor, ErbB-3