Therapies based on inhibitors of the epidermal growth factor receptor: reaching for the future

Arlhee Díaz, Agustín Lage
2007 Biotecnología Aplicada   unpublished
The key role played by the epidermal growth factor receptor (EGFR) in different types of solid tumors have turned this molecule into an important target for rational drug design. The contribution of EGFR-related signaling pathways to the promotion of tumorigenic processes, including cell proliferation, angiogenesis, and resistance to apoptosis has been well established. Two classes of anti-EGFR agents currently in late-stage clinical testing include monoclonal antibodies against the
more » ... nst the extracellular domain of EGFR (Cetuximab, Nimotuzumab) and small-molecule tyrosine kinase inhibitors, which block the enzymatic activity of the receptor (Gefitinib, Erlotinib). In spite of the considerable amount of information gathered from clinical trials with these compounds, important questions such as reliable surrogate markers to predict response to the treatment, or the optimal sequence and combination of these agents with conventional therapies must still be addressed. It has become imperative to identify and validate predictive factors allowing the selection of those patients most likely to respond to EGFR inhibitors, such as mutations that confer resistance versus those associated with sensitivity. A better understanding of the molecular mechanisms associated with antitumoral activity will be useful for predicting the results of the interaction of these agents with traditional therapies, in order to prevent antagonic or redundant effects that do not increase antitumoral activity. Finally, the benefits derived from EGFR inhibitors as first-line therapy in selected populations, and the optimal doses and delivery routes to the tumor site resulting in optimal target modulation should be established by the current research.