Inhibition of receptor tyrosine kinase-based signal transduction as specific target for cancer treatment.
Every cell in a multicellular organism receives signals from the extracellular matrix and neighboring cells. These signals are transmitted, via transmembrane receptors and cascade proteins of the intracellular message system, inside the cell and often to the nucleus, regulating almost every physiological function of the cell. Protein tyrosine kinases constitute a family of receptors that regulate major cellular events, such as cell proliferation, differentiation, cell adhesion and apoptosis. Mutant tyrosine kinases and/or their aberrant activity are associated with human cancer and other hyper-proliferative diseases. Strategies for inhibition of aberrant tyrosine kinase activity, such as antisense oligonucleotides, antigenic stimulation and small molecular inhibitors have been developed. STI571, a phenylaminopyrimidine derivative, is considered to be the pioneer of the small molecular inhibitors available to date. It is a successful tyrosine kinase inhibitor, which is currently approved and used for the treatment of chronic myelogenous leukemia and gastrointestinal tumors. In this article we review the mechanisms of cell signaling, the signal transduction pathways related to tyrosine kinases, their relationship with cancer, and the strategies developed to inhibit the aberrant tyrosine kinase receptor-based signal transduction. Drug resistance and future perspectives for combination therapies are also discussed.
Roussidis
Andreas E
AE
Department of Chemistry, Section of Organic Chemistry, Biochemistry and Natural Products, Laboratory of Biochemistry, University of Patras, 261 10 Patras, Greece.
Karamanos
Nikos K
NK
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004359:Drug Therapy, Combination; D006801:Humans; D000068877:Imatinib Mesylate; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D010879:Piperazines; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D020794:Receptor Protein-Tyrosine Kinases