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      Receptor tyrosine kinase (c-Kit) inhibitors: a potential therapeutic target in cancer cells

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          Abstract

          c-Kit, a receptor tyrosine kinase, is involved in intracellular signaling, and the mutated form of c-Kit plays a crucial role in occurrence of some cancers. The function of c-Kit has led to the concept that inhibiting c-Kit kinase activity can be a target for cancer therapy. The promising results of inhibition of c-Kit for treatment of cancers have been observed in some cancers such as gastrointestinal stromal tumor, acute myeloid leukemia, melanoma, and other tumors, and these results have encouraged attempts toward improvement of using c-Kit as a capable target for cancer therapy. This paper presents the findings of previous studies regarding c-Kit as a receptor tyrosine kinase and an oncogene, as well as its gene targets and signaling pathways in normal and cancer cells. The c-Kit gene location, protein structure, and the role of c-Kit in normal cell have been discussed. Comprehending the molecular mechanism underlying c-Kit-mediated tumorogenesis is consequently essential and may lead to the identification of future novel drug targets. The potential mechanisms by which c-Kit induces cellular transformation have been described. This study aims to elucidate the function of c-Kit for future cancer therapy. In addition, it has c-Kit inhibitor drug properties and their functions have been listed in tables and demonstrated in schematic pictures. This review also has collected previous studies that targeted c-Kit as a novel strategy for cancer therapy. This paper further emphasizes the advantages of this approach, as well as the limitations that must be addressed in the future. Finally, although c-Kit is an attractive target for cancer therapy, based on the outcomes of treatment of patients with c-Kit inhibitors, it is unlikely that Kit inhibitors alone can lead to cure. It seems that c-Kit mutations alone are not sufficient for tumorogenesis, but do play a crucial role in cancer occurrence.

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          Most cited references 142

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          Signal transduction by receptors with tyrosine kinase activity.

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            Protein modules and signalling networks.

            Communication between cells assumes particular importance in multicellular organisms. The growth, migration and differentiation of cells in the embryo, and their organization into specific tissues, depend on signals transmitted from one cell to another. In the adult, cell signalling orchestrates normal cellular behaviour and responses to wounding and infection. The consequences of breakdowns in this signalling underlie cancer, diabetes and disorders of the immune and cardiovascular systems. Conserved protein domains that act as key regulatory participants in many of these different signalling pathways are highlighted.
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              The development of imatinib as a therapeutic agent for chronic myeloid leukemia.

              Imatinib has revolutionized drug therapy of chronic myeloid leukemia (CML). Preclinical studies were promising but the results of clinical trials by far exceeded expectations. Responses in chronic phase are unprecedented, with rates of complete cytogenetic response (CCR) of more than 40% in patients after failure of interferon-alpha (IFN) and more than 80% in newly diagnosed patients, a level of efficacy that led to regulatory approval in record time. While most of these responses are stable, resistance to treatment after an initial response is common in more advanced phases of the disease. Mutations in the kinase domain (KD) of BCR-ABL that impair imatinib binding have been identified as the leading cause of resistance. Patients with CCR who achieve a profound reduction of BCR-ABL mRNA have a very low risk of disease progression. However, residual disease usually remains detectable with reverse transcription-polymerase chain reaction (RT-PCR), indicating that disease eradication may pose a significant challenge. The mechanisms underlying the persistence of minimal residual disease are unknown. In this manuscript, we review the preclinical and clinical development of imatinib for the therapy of CML, resistance and strategies that may help to eliminate resistant or residual leukemia.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                Drug Design, Development and Therapy
                Drug Design, Development and Therapy
                Dove Medical Press
                1177-8881
                2016
                01 August 2016
                : 10
                : 2443-2459
                Affiliations
                [1 ]Department of Pharmacy, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
                [2 ]Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-e Pajoohesh
                [3 ]Medical Genetics Department, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
                [4 ]Department of Urology
                [5 ]Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota
                [6 ]Section of Molecular Therapeutics & Cancer Health Disparity, The Hormel Institute, Austin, MN, USA
                [7 ]Clinical Investigation Centre, University Malaya Medical Centre, Lembah Pantai, Kuala Lumpur, Malaysia
                Author notes
                Correspondence: Hasniza Zaman Huri, Department of Pharmacy, Faculty of Medicine, Level 3, Block R., University of Malaya, 50603 KL, Malaysia, Tel +60 3 7967 6659, Fax +60 3 7954 1904, Email hasnizazh@ 123456um.edu.my
                Behnam Kamalidehghan, Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Shahrak-e Pajoohesh, Km 15, PO Box: 14965/161, Tehran, Iran, Email kamalidehghan.behnam@ 123456gmail.com
                Article
                dddt-10-2443
                10.2147/DDDT.S89114
                4975146
                27536065
                © 2016 Abbaspour Babaei et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

                Categories
                Review

                Pharmacology & Pharmaceutical medicine

                cancer therapy, c-kit, cancer, oncogene

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