Molecular biology of epidermal growth factor receptor inhibition for cancer therapy.
Understanding the role of the epidermal growth factor receptor (EGFR) in cellular signalling processes underlying malignancy has enabled the development of rationally designed EGFR-targeted therapeutics. Strategies have been devised to interfere with the EGFR signalling at three different levels: at the extracellular level, competing with ligand binding; at the intracellular level, inhibiting the activation of the tyrosine kinase; or at the mRNA level, modulating the expression of the EGFR protein. Each of these strategies has proven to have an antitumour effect mediated by events such as inhibition of cell proliferation, induction of apoptosis, decrease of cellular invasion and migration; and/or inhibition of angiogenesis. Furthermore, the combination of these strategies with traditional chemotherapy or radiotherapy has generally resulted in enhanced antitumour effects. Likewise, the benefit of interfering simultaneously with different signalling pathways has been documented to improve tumour growth inhibition. These preclinical results have encouraged clinical studies that led to the FDA approval of three drugs. However, finding the perfect strategy for each individual patient appears to be a limiting factor, demanding further research to be able to generate relevant molecular expression profiles on a case-to-case basis. Taken together, a successful EGFR inhibition will require a better understanding of signalling pathways in combination with the development of rationally designed effective molecules.
Oliveira
Sabrina
S
Institute for Pharmaceutical Sciences, Department of Pharmaceutics, Utrecht University, PO Box 80.082, 3508 TB Utrecht, The Netherlands. S.Oliveira@pharm.uu.nl
van Bergen en Henegouwen
Paul M P
PM
Storm
Gert
G
Schiffelers
Raymond M
RM
D000818:Animals; D049109:Cell Proliferation; D003131:Combined Modality Therapy; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy*; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction
D012333:RNA, Messenger; D066246:ErbB Receptors