ERBB receptors and cancer: the complexity of targeted inhibitors

Abstract

The family of ERBB or epidermal growth factor (EGF) receptors includes four members: EGFR/ERBB1, ERBB2, ERBB3 and ERBB4. EGFR and ERBB2 are involved in development of numerous types of human cancer and they have been intensely pursued as therapeutic targets. Two important types of ERBB inhibitor are in clinical use: humanized antibodies directed against the extracellular domain of EGFR or ERBB2, and small-molecule tyrosine-kinase inhibitors (TKIs) that compete with ATP in the tyrosine-kinase domain of the receptor. In preclinical models, treatment of tumour cells with ERBB-directed TKIs and antibodies rapidly downregulates phosphatidylinositol-3-kinase–AKT, mitogen-activated protein kinase, SRC, and signal transducer and activator of transcription (STAT) signalling, and blocks the proliferation of tumour cells. In the clinic, skin biopsies (surrogate tissue), and to a limited extent tumours, have been analysed for the molecular consequences of treatment with ERBB inhibitors. ERBB-directed therapeutics have demonstrated clinical efficacy; however, the antitumour effects are often not as strong as predicted from preclinical studies. There are likely to be various reasons why this is so, an important one being that other tumour-cell alterations influence the tumour response to ERBB-targeted inhibitors. Therefore, rational drug-combination strategies have great potential to combat the complexity of tumour biology.