J. Mcintyre, J. Castaǹer, P. Leeson
2005
Citations
0
Influential Citations
13
Citations
Journal
Drugs of The Future
Abstract
Dysfunction of intracellular signaling pathways has been implicated in the development and progression of cancer. Canertinib is an irreversible small-molecule tyrosine kinase inhibitor that blocks signal transduction through all four members of the ErbB (or epidermal growth factor [EGF]) family and is in development for the treatment of advanced nonhematological cancers. Canertinib inhibited ligand-dependent tyrosine phosphorylation in cell lines expressing ErbB receptor kinases. In mice bearing advanced human epidermoid A-431 xenografts, suppression of EGF receptor tyrosine phosphorylation correlated with antitumor activity. In vitro activity of canertinib was demonstrated against a range of tumor types, including glioblastoma, mesothelioma, non-small cell lung cancer, mammary tumors and orthotopic bladder tumors. A radiosensitizing effect was also demonstrated in a number of different carcinoma cell lines, as well as synergistic activity in combination with cisplatin, topotecan or gemcitabine. In clinical studies, canertinib has demonstrated an acceptable tolerability profile, with the most frequently reported toxicities being gastrointestinal symptoms and skin reactions. Although few objective responses were observed in these preliminary studies, a number of patients with different tumor types achieved stable disease for varying lengths of time and the clinical efficacy of canertinib is being evaluated in ongoing phase II studies.