Gontarewicz Artur, Brümmendorf Tim H
Department of Oncology and Hematology, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Recent Results Cancer Res. 2010;184:199-214. doi: 10.1007/978-3-642-01222-8_14.
The Aurora kinases belong to a family of highly conserved serine/threonine protein kinases. They play an essential role as key mitotic regulators, controlling entry into mitosis, centrosome function, chromosome assembly, and segregation. As many other regulators of mitosis, Aurora kinases are frequently found to be aberrantly overexpressed in cancer cells. Therefore, these proteins have become an attractive target for the development of new anticancer therapies. In fact, several small-molecule inhibitors of Aurora kinases have already been developed and some of them have shown promising clinical efficacy in a number of human tumors in Phase I and II clinical trials. Among those, one of the most advanced clinical compound currently is Danusertib (formerly PHA-739358), which exhibits inhibitory activity against all known Aurora kinases as well as other cancer-relevant kinases such as the Bcr-Abl tyrosine kinase, including its multidrug-resistant T315I mutant. This mutation is responsible for up to 25% of all clinically observed resistances in CML patients undergoing Imatinib therapy. However, this particular mutation is predicted to play an even more important clinical role in the future, since in addition to Imatinib, it also confers resistance to second-generation Bcr-Abl inhibitors such as Nilotinib, Dasatinib, and Bosutinib. Therefore, combined Aurora and Bcr-Abl inhibition (the latter including high-grade resistance conferring mutations) with compounds such as Danusertib represents a promising new strategy for treatment of Bcr-Abl positive leukemias, especially those in second and third line of treatment.
极光激酶属于高度保守的丝氨酸/苏氨酸蛋白激酶家族。它们作为关键的有丝分裂调节因子发挥着至关重要的作用，控制着进入有丝分裂、中心体功能、染色体组装和分离。与许多其他有丝分裂调节因子一样，极光激酶在癌细胞中经常被异常过度表达。因此，这些蛋白质已成为开发新型抗癌疗法的有吸引力的靶点。事实上，几种极光激酶的小分子抑制剂已经被开发出来，其中一些在I期和II期临床试验中已在多种人类肿瘤中显示出有前景的临床疗效。其中，目前最先进的临床化合物之一是达沙替尼（原名PHA-739358），它对所有已知的极光激酶以及其他与癌症相关的激酶如Bcr-Abl酪氨酸激酶，包括其多药耐药T315I突变体，都具有抑制活性。这种突变在接受伊马替尼治疗的慢性粒细胞白血病患者中，占所有临床观察到的耐药性的25%。然而，预计这种特定突变在未来将发挥更重要的临床作用，因为除了伊马替尼外，它还赋予对第二代Bcr-Abl抑制剂如尼罗替尼、达沙替尼和博舒替尼的耐药性。因此，用达沙替尼等化合物联合抑制极光激酶和Bcr-Abl（后者包括赋予高度耐药性的突变）代表了一种有前景的治疗Bcr-Abl阳性白血病的新策略，特别是在二线和三线治疗中。
