Abstract
Chemotherapeutic and cytotoxic drugs are widely used in the treatment of cancer. In spite of the improvements in the life quality of patients, their effectiveness is compromised by several disadvantages. This represents a demand for developing new effective strategies with focusing on tumor cells and minimum side effects. Targeted cancer therapies and personalized medicine have been defined as a new type of emerging treatments. Small molecule inhibitors (SMIs) are among the most effective drugs for targeted cancer therapy. The growing number of approved SMIs of receptor tyrosine kinases (RTKs) i.e., tyrosine kinase inhibitors (TKIs) in the clinical oncology imply the increasing attention and application of these therapeutic tools. Most of the current approved RTK–TKIs in preclinical and clinical settings are multi-targeted inhibitors with several side effects. Only a few specific/selective RTK–TKIs have been developed for the treatment of cancer patients. Specific/selective RTK–TKIs have shown less deleterious effects compared to multi-targeted inhibitors. This review intends to highlight the importance of specific/selective TKIs for future development with less side effects and more manageable agents. This article provides an overview of: (1) the characteristics and function of RTKs and TKIs; (2) the recent advances in the improvement of specific/selective RTK–TKIs in preclinical or clinical settings; and (3) emerging RTKs for targeted cancer therapies by TKIs.
Highlights
Cancer is a complex disorder of the uncontrolled proliferation of cells
Due to the lack of cumulative data on selective/specific tyrosine kinase inhibitors (TKIs), this review summarizes the recent findings regarding more specific/selective receptor tyrosine kinases (RTKs)–TKIs that are approved by authorities or are in preclinical and clinical settings
Gefitinib (ZD1839, Iressa) [36] and erlotinib (OSI-774, Tarceva) [37] belong to the first generation of TKIs and are selective Epithelial Growth Factor Receptor (EGFR)–TKIs that were approved on May 2003 and November 2004 for the treatment of non-small cell lung cancer (NSCLC) patients, respectively (Table 2) [30,38]
Summary
Cancer is a complex disorder of the uncontrolled proliferation of cells. Currently, eight hallmarks explain the typical capabilities acquired by tumor cells in the process of tumorigenesis [1]. Monoclonal antibodies (mAbs) and small-molecule inhibitors (SMIs) of tyrosine kinase activity (TKIs) are ideal candidates which target tumor cells via binding to cell-surface antigens and intracellular molecules, respectively [10]. There has been a significant progress in developing specific/selective TKIs for targeted cancer therapy. Most of the FDA approved TKIs for the treatment of cancer are multi-targeted inhibitors of several intracellular tyrosine kinases (Table 3), and a few inhibit the members of a family. EGFR members are abnormally activated by several mechanisms like receptor over-expression, mutation, ligand-dependent receptor dimerization, ligand-independent stimulation, and are associated with the development of tumors of epithelial origin, including non-small cell lung cancer (NSCLC) [30], breast [31], colorectal [32], and pancreatic cancer [33]. Specific/selective inhibition of EGFR is an ideal approach to cancer treatment
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