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首页> 外文期刊>Cell cycle >A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment.
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A cell-based screening strategy that predicts mutations in oncogenic tyrosine kinases: implications for clinical resistance in targeted cancer treatment.

机译：一种基于细胞的筛选策略，可预测致癌酪氨酸激酶的突变：对靶向癌症治疗的临床耐药性的影响。

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摘要

The discovery of tyrosine kinases that, once deregulated, can cause malignancy, allowed the development of specifically acting anti-cancer compounds. In chronic myeloid leukaemia (CML), the Bcr-Abl kinase inhibitor imatinib (STI571, Gleevec) induces impressive response rates. However, resistance occurs especially in advanced phase CML and Ph+ ALL, primarily as a consequence of point mutations within the Bcr-Abl kinase domain that prevent imatinib from binding. To overcome imatinib resistance, alternative Abl kinase inhibitors are finding their way into clinical trials. However, it is likely that resistance to second-generation compounds will occur as well. Therefore, it will be critical to determine specific resistance profiles for each particular compound. We recently developed a cell-based screening strategy that allows one to predict the pattern and relative abundance of Bcr-Abl resistance mutations emerging in the presence of imatinib or an alternative Abl-kinase inhibitor. Using this strategy, the findings in inhibitor resistant sublines reflect observations made in CML patients with imatinib resistance, including Bcr-Abl mutations, amplification of the Bcr-Abl gene, and overexpression of the Bcr-Abl protein. We here provide a detailed methodological description, and discuss the implications of this strategy for different clinically relevant oncogenic tyrosine kinases.
机译：酪氨酸激酶一旦失调，就会引起恶性肿瘤的发现，使得特异性作用的抗癌化合物得以发展。在慢性粒细胞白血病（CML）中，Bcr-Abl激酶抑制剂伊马替尼（STI571，Gleevec）引起令人印象深刻的反应率。但是，耐药尤其在晚期CML和Ph + ALL中发生，主要是由于Bcr-Abl激酶结构域内的点突变阻止了伊马替尼的结合。为了克服伊马替尼耐药性，替代性的Abl激酶抑制剂正在进入临床试验。但是，也有可能对第二代化合物产生抗药性。因此，确定每种特定化合物的特定电阻曲线至关重要。我们最近开发了一种基于细胞的筛选策略，该策略可以预测在伊马替尼或其他Abl激酶抑制剂存在下出现的Bcr-Abl抗性突变的模式和相对丰度。使用这种策略，抑制剂抗性亚系中的发现反映了伊马替尼耐药的CML患者的观察结果，包括Bcr-Abl突变，Bcr-Abl基因的扩增和Bcr-Abl蛋白的过表达。我们在这里提供了详细的方法学说明，并讨论了该策略对不同临床相关致癌酪氨酸激酶的影响。

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