Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance.
Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia-From Molecular Mechanisms to Clinical Relevance.
复制标题
慢性粒细胞白血病对酪氨酸激酶抑制剂的耐药-从分子机制到临床相关性。
DOI：
10.3390/cancers13194820
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发表时间：
2021-09-26
期刊：
影响因子：
5.2
通讯作者：
Sarmento Ribeiro AB
中科院分区：
文献类型：
--
作者：
Alves R;Gonçalves AC;Rutella S;Almeida AM;De Las Rivas J;Trougakos IP;Sarmento Ribeiro AB
慢性髓系白血病(CML)是一种与分子突变相关的骨髓增生性肿瘤，融合基因BCR-ABL1编码酪氨酸激酶癌蛋白BCR-ABL1。这导致了酪氨酸激酶抑制剂(TKI)的开发，伊马替尼是第一个获得批准的TKI。尽管绝大多数慢性粒细胞白血病患者对伊马替尼有反应，但对这种靶向治疗的耐药性导致治疗失败和复发。在这里，我们回顾了TKI耐药的分子机制和其他因素(如患者依从性)，获得这些机制的方法，以及规避CML中TKI耐药的可能的治疗方法。对靶向治疗的抗药性是一个复杂和多因素的过程，最终会选择一个能够逃避治疗的癌症克隆。慢性粒细胞白血病(CML)是第一个被认为与t(9；22)(q34；q11)基因改变相关的恶性肿瘤。这种易位起源于BCR-ABL1融合基因，编码细胞质嵌合的BCR-ABL1蛋白，显示出异常高的酪氨酸激酶活性。虽然绝大多数慢性粒细胞白血病患者对酪氨酸激酶抑制剂(TKI)伊马替尼有反应，但耐药性可能发生在从头开始或治疗期间。在慢性粒细胞白血病中，TKI的耐药机制通常分为BCR-ABL1依赖机制和独立机制。此外，患者对治疗的依从性/依从性对慢性粒细胞白血病的管理至关重要。具有更高敏感性的技术，如NGS和dPCR，人工智能(AI)技术的使用，以及数学建模和计算预测方法的发展，可以揭示CML患者耐药的潜在机制，并有助于设计更有效的治疗策略来提高CML患者的药物疗效。在这里，我们回顾了慢性粒细胞白血病对TKI耐药的分子机制和其他因素，以及获得这些机制的新方法，以及规避TKI耐药的治疗方法。
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasia associated with a molecular alteration, the fusion gene BCR-ABL1, that encodes the tyrosine kinase oncoprotein BCR-ABL1. This led to the development of tyrosine kinase inhibitors (TKI), with Imatinib being the first TKI approved. Although the vast majority of CML patients respond to Imatinib, resistance to this targeted therapy contributes to therapeutic failure and relapse. Here we review the molecular mechanisms and other factors (e.g., patient adherence) involved in TKI resistance, the methodologies to access these mechanisms, and the possible therapeutic approaches to circumvent TKI resistance in CML. Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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von Bubnoff, N.
DOI：
10.1016/j.ddtec.2014.03.003
发表时间：
2014-03-01
期刊：
Drug discovery today. Technologies
影响因子：
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作者：
Balabanov, Stefan;Braig, Melanie;Brummendorf, Tim H
通讯作者：
Brummendorf, Tim H