Mechanisms of Clinical Resistance to Small Molecule Tyrosine Kinase Inhibitors Targeting Oncogenic Tyrosine Kinases
作者:
Heiko van der Kuip,
Lara Wohlbold,
Carsten Oetzel,
Matthias Schwab,
Walter E Aulitzky,
期刊:
American Journal of PharmacoGenomics
(ADIS Available online 2005)
卷期:
Volume 5,
issue 2
页码: 101-112
ISSN:1175-2203
年代: 2005
出版商: ADIS
关键词: Tyrosine kinase inhibitors, general;Cancer, general;Drug resistance;Genomics
数据来源: ADIS
摘要:
A number of highly specific small molecule inhibitors of oncogenic tyrosine kinases have been developed and may potentially improve the treatment of different malignant diseases. However, it became rapidly evident that multiple resistance mechanisms compromise the successful clinical application of these inhibitors, particularly in advanced solid tumors.To develop efficient therapeutic strategies with small molecule inhibitors, one must understand the causes for treatment failure. Three different types of resistance to small molecule inhibitors of oncogenic tyrosine kinases have been observed. The malignant phenotype may be independent of the activity of the target kinase (target-independent resistance). Alternatively, overexpression or mutation of the target kinase can counteract the inhibition of oncogenic tyrosine kinases (target-dependent resistance). Finally, alterations of drug transporters or drug-metabolizing pathways may block the bioavailability of the tyrosine kinase inhibitors (drug-dependent resistance). This article reviews the current knowledge of clinical resistance to small molecule inhibitors approved for treatment of cancer patients.
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