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

Rastislav Tamaskovic, Martin Schwill, Gabriela Nagy-Davidescu, Christian Jost, Dagmar C. Schaefer, Wouter P. R. Verdurmen, Jonas V. Schaefer, Annemarie Honegger and Andreas Plückthun ()
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Rastislav Tamaskovic: University of Zurich
Martin Schwill: University of Zurich
Gabriela Nagy-Davidescu: University of Zurich
Christian Jost: University of Zurich
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

Nature Communications, 2016, vol. 7, issue 1, 1-18

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms11672

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