title: Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS-p110 crosstalk.
abstract: Compensatory mechanisms, such as relief of AKT-ErbB3-negative feedback, are known to desensitize ErbB2-dependent tumours to targeted therapy. Here we describe an adaptation mechanism leading to reactivation of the PI3K/AKT pathway during trastuzumab treatment, which occurs independently of ErbB3 re-phosphorylation. This signalling bypass of phospho-ErbB3 operates in ErbB2-overexpressing cells via RAS-PI3K crosstalk and is attributable to active ErbB2 homodimers. As demonstrated by dual blockade of ErbB2/RAS and ErbB3 by means of pharmacological inhibition, RNA interference or by specific protein binders obstructing the RAS-p110α interaction, both routes must be blocked to prevent reactivation of the PI3K/AKT pathway. Applying these general principles, we developed biparatopic designed ankyrin repeat proteins (DARPins) trapping ErbB2 in a dimerization-incompetent state, which entail pan-ErbB inhibition and a permanent OFF state in the oncogenic signalling, thereby triggering extensive apoptosis in ErbB2-addicted tumours. Thus, these novel insights into mechanisms underlying network robustness provide a guide for overcoming adaptation response to ErbB2/ErbB3-targeted therapy.
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Rastislav
authors.initials: R
authors.lastname: Tamaskovic
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Martin
authors.initials: M
authors.lastname: Schwill
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Nagy-Davidescu
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Jost
authors.affiliation: Institute of Laboratory Animal Science, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Dagmar C
authors.initials: DC
authors.lastname: Schaefer
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Wouter P R
authors.initials: WP
authors.lastname: Verdurmen
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Jonas V
authors.initials: JV
authors.lastname: Schaefer
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Annemarie
authors.initials: A
authors.lastname: Honegger
authors.affiliation: Department of Biochemistry, University of Zurich, Winterthurerstr. 190, Zurich 8057, Switzerland.
authors.forename: Andreas
authors.initials: A
authors.lastname: Plückthun
mesh_terms: D017089:Ankyrin Repeat; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology; D017209:Apoptosis; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D006801:Humans; D060066:Protein Interaction Maps; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D000068878:Trastuzumab / Q000494:pharmacology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D058534:Class I Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; D018631:ras Proteins; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human; C485206:pertuzumab