Figure 10: Model of induction of apoptosis and adaptive resistance in response to ErbB2 blockade. | Nature Communications

Figure 10: Model of induction of apoptosis and adaptive resistance in response to ErbB2 blockade.

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

Figure 10

(a) Overexpression of ErbB2 is sufficient to activate ErbB2 and ErbB3 in the absence of ligands and drives tumour growth predominantly via the ErbB2/ErbB3/PI3K/AKT signalling axis. This signalling route constitutively suppresses negative feedback regulation between AKT and ErbB3, which is however relieved upon blockade of ErbB2/3 receptors or the downstream signalling pathways. (b) Trastuzumab treatment induces partial ErbB2 blockade by selectively interfering with the ligand-independent ErbB2/ErbB3 heterodimers, thereby uncoupling ErbB3 from PI3K/AKT reactivation. Here we identified a novel adaptation response that emanates from ErbB2/RAS and bypasses ErbB3 for the activation of PI3K/AKT signalling. (c) Biparatopic DARPins obstruct all ligand-dependent and ligand-independent complexes of ErbB2. Such a pan-ErbB2 inhibition blocks PI3K/AKT signalling cascade and consecutive adaptive responses, leading to a stable OFF state of the ErbB oncogenic network. Consequently, intrinsic apoptosis is induced which prevents emergence of adaptive resistance.

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