A Third Shot at EGFR: New Opportunities in Cancer Therapy.

Epidermal growth factor receptor (EGFR) inhibitors were among the first type of targeted agents discovered in cancer and currently constitute the standard of care for a wide range of lung and colon malignancies. However, the therapeutic progress achieved with these drugs has been accompanied by the identification of an ever-increasing number of acquired resistance mechanisms that inevitably appear in nearly all patients. Increased knowledge on EGFR biochemistry, cellular crosstalk, and resistance pathways provides an opportunity to establish effective combination therapies and discover novel-acting inhibitors that prevent or overcome therapeutic resistance. One such strategy is the selective blockade of circulating growth factors such as EGF. In this review, we address the uses and limitations of approved EGFR inhibitors and explore the potential of drug combinations and new third avenues to block the activation of the EGFR. The initial excitement over the efficacy of EGFR-targeted drugs (TKIs and mAbs) has been offset by a growing number of drug-resistant mutations that invariably appear in patients; thus novel-acting drugs and synergistic combinations are in high demand. The direct inhibition of the main activating ligand (EGF) is considered a promising strategy and has been explored with other kinase receptors, such as VEGF, FGF, and TGF-β. EGF is a small protein with no active sites and/or binding cavities that can be efficiently drugged using traditional small-molecule approaches and has thus remained a challenging target. Peptides, vaccines, and single-chain antibodies against EGF have recently emerged as a new class of biotherapeutics in the fight against EGFR-driven tumours. [ABSTRACT FROM AUTHOR]