Combination of epidermal growth factor receptor inhibitors and antiangiogenic drugs: A model for treatment

The epidermal growth factor receptor (EGFR) autocrine pathway plays a crucial role in human cancer since it contributes to relevant processes in tumor development and progression, including cell proliferation, regulation of apoptotic cell death, angiogenesis and metastatic spread. EGFR-blocking monoclonal antibodies and small-molecule EGFR tyrosine kinase inhibitors have been developed as anticancer drugs. Although anti-EGFR agents are active in a subset of cancer patients, constitutive resistance in a large number of patients and the development of acquired resistance in initially responding patients are a relevant clinical issue. A major problem is that intrinsic and/or acquired resistance can occur, and it could be due to the activation of alternative cancer cell growth controlling pathways. One mechanism linked to acquired resistance to EGFR-inhibitor treatment, in particular, is the activation of uncontrolled, tumor-induced angiogenesis through an increase in vascular endothelial growth factor (VEGF) secretion by cancer cells. Significant and sustained antitumor activity in this context can be obtained by combining selective anti-EGFR drugs with antiangiogenic agents. In this review, we focus on the preclinical and clinical evidence showing that an approach combining anti-EGFR and antiangiogenic drugs is feasible and could represent a paradigm for a rational combined multi-targeted treatment of cancer.