Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies.
Targeting mutated protein tyrosine kinases and their signaling pathways in hematologic malignancies.
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DOI：
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发表时间：
2005
期刊：
影响因子：
10.1
通讯作者：
Y. Chalandon;J. Schwaller
中科院分区：
文献类型：
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作者：
Y. Chalandon;J. Schwaller
在过去的十年中，在阐明白血病发生的机制方面取得了重大进展，特别是在解除对蛋白酪氨酸激酶（PTK）激活的调节方面。这一进展导致了小分子的发展，专门抑制异常活化的激酶。这种靶向治疗的第一个例子是甲磺酸伊马替尼，这是一种BCR-ABL融合基因抑制剂，在超过90%的费城阳性（Ph+）慢性髓性白血病（CML）患者和20-30%的Ph+急性淋巴细胞白血病（ALL）患者中发现。伊马替尼治疗CML取得的优异临床效果彻底改变了该病的治疗方式，伊马替尼现已成为治疗新诊断CML的金标准。这激发了开发靶向PTK疗法的巨大努力，该疗法基于40多种染色体易位的存在，这些易位导致与各种血液恶性肿瘤相关的12种不同PTK的失调。不受调控的PTK也参与了急性白血病的发病机制，这一点被频繁发生的导致FLT3组成性激活的突变所强调。实验和临床证据支持基于组成活性PTK与转录调节因子突变合作的急性白血病模型。在这里，我们回顾突变PTK对各种血液恶性肿瘤发病机制的一般影响。我们还讨论了新的靶向治疗和策略的发展，通过靶向下游信号介质来规避与耐药出现相关的日益严重的问题，这些信号介质对于解除管制的PTK转化至关重要。
Over the last decade, major advances have been made in the elucidation of mechanisms involved in leukemogenesis, and this is particularly true with regard to deregulated protein tyrosine kinase (PTK) activation. This progress had led to the development of small molecules that specifically inhibit the abnormally activated kinase. The first example of such targeted therapy is imatinib-mesylate, an inhibitor of the BCR-ABL fusion gene that is found in more than 90% of patients with Philadelphia positive (Ph+) chronic myeloid leukemia (CML) and in 20-30% of those with Ph+ acute lymphoblastic leukemia (ALL). The excellent clinical results obtained with imatinib in CML have completely changed the therapeutic approach to this disease, and imatinib is now the gold standard for treatment of newly diagnosed CML. This has instigated a tremendous effort to develop targeted PTK therapy based on the presence of over 40 chromosomal translocations that lead to deregulation of 12 different PTK associated with various hematologic malignancies. That deregulated PTK are also involved in the pathogenesis of acute leukemia is underlined by the frequent occurrence of mutations leading to constitutive activation of the FLT3. Experimental as well as clinical evidence supports a model of acute leukemia based on the co-operation of constitutive active PTK with mutations of transcriptional regulators. Here we review the general impact of mutated PTK on the pathogenesis of various hematologic malignancies. We also discuss the development of new targeted therapies and strategies to circumvent the increasing problems related to the emergence of drug resistance by targeting downstream signaling mediators that are essential for transformation by deregulated PTK.