Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia.
Current aspects in resistance against tyrosine kinase inhibitors in chronic myelogenous leukemia.
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DOI：
10.1016/j.ddtec.2014.03.003
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发表时间：
2014-03-01
期刊：
影响因子：
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通讯作者：
Brummendorf, Tim H
中科院分区：
文献类型：
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作者：
Balabanov, Stefan;Braig, Melanie;Brummendorf, Tim H
对酪氨酸激酶抑制剂（TKI）的耐药性代表了慢性粒细胞白血病（CML）治疗中的一个相关临床问题。根据其对BCR-ABL突变谱的活性（已证明BCR-ABL突变是伊马替尼耐药的最主要机制），新TKI已被分类为第二代（如尼洛替尼、达沙替尼和博舒替尼）或第三代（也涵盖T315 I，如泊那替尼）TKI。然而，BCR-ABL突变仅占TKI治疗失败病例的约一半，并且已经确定了使白血病细胞仍然依赖于BCR-ABL活性或支持白血病细胞的致癌特性而不依赖于BCR-ABL信号传导的其他机制。详细了解不同的潜在耐药机制将是最终克服临床耐药性和未来成功使用靶向抑制剂定制组合的先决条件。
Resistance against tyrosine kinase inhibitors (TKIs) represents a relevant clinical problem in treatment of chronic myelogenous leukemia (CML). On the basis of their activity against the spectrum of BCR-ABL mutations that have shown to be the most prominent mechanism of resistance to imatinib, new TKIs have been classified as second generation (such as nilotinib, dasatinib and bosutinib) or third generation (also cover- ing T315I such as ponatinib) TKIs. However, mutations in BCR-ABL only account for about half of the cases of treatment failure under TKI and other mechanisms either rendering the leukemic cells still dependent of BCR-ABL activity or supporting oncogenic properties of the leukemic cells independent of BCR-ABL signaling have been identified. A detailed understanding of the different underlying resistance mechanisms will be the prerequisite to eventually overcome clinical resistance and for the successful use of tailored combinations of targeted inhibitors in the future.