BIBW-2992, a dual receptor tyrosine kinase inhibitor for the treatment of solid tumors.
ABSTRACT 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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ABSTRACT: Lung cancer remains the most lethal malignancy in the world. Despite improvements in surgical treatment, systemic therapy, and radiotherapy, the 5-year survival rate for all patients diagnosed with lung cancer remains between 15 and 20%. Newer therapeutic strategies rely on specific molecular alterations, or biomarkers, that provide opportunities for a personalized approach to specific patient populations. Classification of lung cancer is becoming increasingly focused on these biomarkers, which renders the term "non-small cell lung" cancer less clinically useful. Non-small cell lung cancer is now recognized as a complex malignancy and its molecular and genomic diversity allows for patient-centered treatment options. Here, we review advances in targeted treatment of lung adenocarcinoma with respect to five clinically relevant biomarkers - EGFR, ALK, MET, ROS-1, and KRAS.Frontiers in Oncology 08/2014; 4:204. DOI:10.3389/fonc.2014.00204
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ABSTRACT: Cancer stem-like cells (CSC) have garnered significant attention as a therapeutic focus, based on evidence they may represent an etiologic root of treatment-resistant cells. Indeed, expression of the multidrug resistance protein ABCG2 confers chemoresistance to CSC where it serves as a potential biomarker and therapeutic target. Here we show that afatinib, a small molecule inhibitor of the tyrosine kinases EGFR, HER-2 and HER-4, preferentially eliminated side population (SP) cells with CSC character, in both cell lines or patient-derived leukemia cells, by decreasing ABCG2 expression. In these cells afatinib also acted in parallel to suppress self-renewal capacity and tumorigenicity. Combining afatinib with the DNA damaging drug topotecan enhanced the antitumor effect of topotecan in vitro and in vivo. Mechanistic investigations suggested that ABCG2 suppression by afatinib did not proceed by proteolysis through the ubiquitin-dependent proteosome, lysosome or calpain. Instead, we found that afatinib increased DNA methyltransferase activity, thereby leading to methylation of the ABCG2 promoter and to a decrease in ABCG2 message level. Taken together, our results advocate the use of afatinib in combination with conventional chemotherapeutic drugs to improve efficacy by improving CSC eradication.Cancer Research 06/2014; 74(16). DOI:10.1158/0008-5472.CAN-13-3553 · 9.28 Impact Factor
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ABSTRACT: Lung cancer is the second most common type of cancer and it has the highest mortality rate worldwide. The purpose of this paper is to analyse the evolutionary growth of knowledge of radical innovations to treat lung cancer which are generating a revolution in clinical practice. The patterns of these new anticancer drugs are evolving through an allometric process of knowledge growth, driven by scientific and technological advances in genetics, genomics and proteomics as well as by multiplicity of learning mechanisms in clinical research and practice. This study shows that traditional chemotherapy agents seem to have reached the maturity phase in the treatment of advanced non-small cell lung cancer because of the introduction of groundbreaking anticancer drugs. The current debate concerns uncertainties about the long-term effects of these radical innovations on carcinogenesis, the high cost of these drugs, and shrinking healthcare budgets. Nevertheless, these innovative treatments generate several benefits in terms of higher survival rate and quality of life. In addition, the structure, characteristics, and properties of the path-breaking technological paradigm to treat lung cancer can lay the foundations for a vital basic scientific framework for effective anticancer treatments in the not-too-distant future.International Journal of Behavioural and Healthcare Research 01/2012; 3(3/4):273 - 290. DOI:10.1504/IJBHR.2012.051406