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Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS–p110 crosstalk

Author

Listed:
  • Rastislav Tamaskovic

    (University of Zurich)

  • Martin Schwill

    (University of Zurich)

  • Gabriela Nagy-Davidescu

    (University of Zurich)

  • Christian Jost

    (University of Zurich
    Present address: Roche Innovation Center Zurich, 8952 Zurich-Schlieren, Switzerland.)

  • Dagmar C. Schaefer

    (Institute of Laboratory Animal Science, University of Zurich)

  • Wouter P. R. Verdurmen

    (University of Zurich)

  • Jonas V. Schaefer

    (University of Zurich)

  • Annemarie Honegger

    (University of Zurich)

  • Andreas Plückthun

    (University of Zurich)

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.

Suggested Citation

  • Rastislav Tamaskovic & Martin Schwill & Gabriela Nagy-Davidescu & Christian Jost & Dagmar C. Schaefer & Wouter P. R. Verdurmen & Jonas V. Schaefer & Annemarie Honegger & Andreas Plückthun, 2016. "Intermolecular biparatopic trapping of ErbB2 prevents compensatory activation of PI3K/AKT via RAS–p110 crosstalk," Nature Communications, Nature, vol. 7(1), pages 1-18, September.
  • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11672
    DOI: 10.1038/ncomms11672
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    Cited by:

    1. Nina E. Weisser & Mario Sanches & Eric Escobar-Cabrera & Jason O’Toole & Elizabeth Whalen & Peter W. Y. Chan & Grant Wickman & Libin Abraham & Kate Choi & Bryant Harbourne & Antonios Samiotakis & Andr, 2023. "An anti-HER2 biparatopic antibody that induces unique HER2 clustering and complement-dependent cytotoxicity," Nature Communications, Nature, vol. 14(1), pages 1-22, December.

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