Minkovsky N, Berezov ABIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors. Curr Opin Investig Drugs 9(12): 1336-1346

University of Pennsylvania, School of Medicine, and Abramson Cancer Center, Department of Pathology and Laboratory Medicine, 252 John Morgan Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
Current opinion in investigational drugs (London, England: 2000) (Impact Factor: 3.55). 01/2009; 9(12):1336-46.
Source: PubMed


The anilino-quinazoline derivative BIBW-2992, which is being developed by Boehringer Ingelheim Corp for the potential treatment of solid tumors, is an oral dual receptor tyrosine kinase inhibitor of human EGF receptor (EGFR) and human epidermal growth factor receptor-2 (HER-2)/neu. EGFR and HER-2/neu activate numerous signaling pathways leading to cancer cell proliferation, survival and migration. In vitro, BIBW-2992 effectively and selectively inhibited EGFR and HER-2/neu and inhibited EGFR and HER-2/neu total tyrosine phosphorylation and tumor cell proliferation in vivo. Importantly, BIBW-2992 was active against tumors overexpressing EGFR with the secondary Thr790Met point mutation, which confers resistance to the first-generation EGFR inhibitors gefitinib and erlotinib. In phase I/II trials, BIBW-2992 was effective in patients with solid tumors, including those with NSCLC tumors activating mutations in the EGFR tyrosine kinase domain. BIBW-2992 was generally well tolerated with the main adverse effects being gastrointestinal or cutaneous disorders. At the time of publication, BIBW-2992 was undergoing phase II trials for NSCLC, breast and prostate cancers, head and neck carcinoma, as well as glioma. BIBW-2992 was granted Fast-Track status by the FDA for NSCLC and was investigated in phase III trials for this indication.

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    • "Lapatinib also binds the inactive conformation of EGFR (Wood et al., 2004), but it has not been active against cancers for which EGFR antibodies or TKIs are approved. Afatinib (Minkovsky and Berezov, 2008) and neratinib (Burstein et al., 2010) are irreversible, covalent HER2/EGFR TKIs with activity against HER2, HER4, "
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    • "The efficacy of the inhibitors is limited in time due to the appearance of cells with resistance mechanisms, in nearly half of the cases a threonine-to-methionine substitution in the EGFR at amino acid position 790 (T790M). Afatinib (BIBW 2992, Boehringer Ingelheim GmbH), is an irreversible inhibitor of both EGFR, HER2 and HER4 kinases and retains some activity in tumors with T790M mutations, but at doses that are a log higher than what is needed for cancers harboring sensitizing mutations [12], [13], [14], [15], [16], [17]. "
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