L8.2 EGFR and HER2: Prototypes of Future Cancer Therapy

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Tumor-specific combinations of oncogenic mutations often release cancer cells from their reliance on growth factors for clonal expansion, angiogenesis, and colonization in distant niches. One important example comprises the epidermal growth factor receptor (EGFR) and its kin, HER2. In tumors, both EGFR and HER2 often display overexpression, internal deletions and point mutations, along with constitutive expression of the respective growth factors (autocrine loops). Accordingly, monoclonal antibodies targeting EGFR or HER2 (e.g., cetuximab and trastuzumab, respectively), as well as kinase inhibitors specific to these receptors (e.g., erlotinib and lapatinib) have been approved for treatment of a broad spectrum of cancer types. Patient's response to molecular targeted drugs like trastuzumab and erlotinib greatly varies and resistance eventually develops due to secondary mutations or to evolvement of drug evasion pathways. To understand the unexpected functional dynamism of signaling processes we apply network configurations and implement the principles of biological robustness. Accordingly, robust biological signaling networks evolved, through gene duplications, from simple, relatively fragile cascades. Architectural features such as layered structures, branching and modularity, as well as functional characteristics (e.g., feedback control circuits), enable fail-safe performance in the face of inactivating perturbations, either internal (mutations) or external (drugs). Viewed from a systems biology perspective, therapy-induced interception of signaling pathways and the common evolvement of drug resistance are respectively considered as manifestations of fragility and plasticity of robust networks. Thus, the systems biology perspective I will present views pathologies as hijackers of biological robustness, as well as offers ways for identifying fragile hubs and strategies to overcome drug resistance.