Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy.
Curr Med Chem. 2012;19(28):4875-84. doi: 10.2174/092986712803341548.
The bi-aryl urea multi-kinase inhibitor Sorafenib (BAY 43-9006, Nexavar) was initially approved for the treatment of unresectable hepatocellular carcinoma and advanced renal cell carcinoma. Eleven years after its first description in PubMed, the therapeutic potential of Sorafenib has been evaluated in an increasing number of studies, mainly focused on solid tumors. More recently, the potential usefullness of Sorafenib has started to emerge also against hematological malignancies. At the molecular level, besides the RAF kinase pathway, which represents the first therapeutic target of Sorafenib, additional kinases, in particular the vascular endothelial growth factor receptor, have been identified as important targets of Sorafenib. A great interest for the potential use of Sorafenib against acute myeloid leukemia (AML) arose when it was demonstrated that a specific mutation of a kinase gene, called FMS-like tyrosin-kinase-3- internal tandem duplication (FLT-3-ITD) and occurring in more than 30% of AML, represents a molecular target of Sorafenib. However, recent phase I and II clinical studies showed that, in spite of its ability to suppress the activity of this mutated kinase, resistence to Sorafenib rapidly occurs in AML, suggesting that Sorafenib will be more effective in combined therapy than used as single drug. Another critical molecular target of Sorafenib is the anti-apoptotic protein Mcl-1. The ability of Sorafenib to rapidly shut-off Mcl-1 in virtually all the hematological malignancies investigated, including the B-chronic lymphocytic leukemia, represents a key element for its antileukemic activity as well as for therapeutic combinations based on Sorafenib. In this respect, it is of particular interest that many chemotherapeutic drugs or innovative anti-neoplastic compounds, such as recombinant TRAIL or inibitors of MDM2 protein, are either unable to down-regulate Mcl-1 or in some instances promote a paradoxical induction of Mcl-1. In this review, the growing evidences for the role of Mcl-1 in mediating the anti-leukemic activity of Sorafenib will be discussed in relationship with promising therapeutic perspectives.
双芳基脲多激酶抑制剂索拉非尼（BAY 43-9006，Nexavar）最初被批准用于治疗不可切除的肝细胞癌和晚期肾细胞癌。在其首次在 PubMed 中描述 11 年后，索拉非尼的治疗潜力已在越来越多的研究中得到评估，主要集中在实体肿瘤上。最近，索拉非尼在血液恶性肿瘤中的潜在用途也开始显现。在分子水平上，除了 RAF 激酶途径，这是索拉非尼的第一个治疗靶点，其他激酶，特别是血管内皮生长因子受体，已被确定为索拉非尼的重要靶点。当证明一种称为 FMS 样酪氨酸激酶-3-内部串联重复（FLT-3-ITD）的激酶基因的特定突变，发生在超过 30%的 AML 中，是索拉非尼的一个分子靶点时，人们对索拉非尼在急性髓细胞白血病（AML）中的潜在应用产生了极大的兴趣。然而，最近的 I 期和 II 期临床试验表明，尽管它能够抑制这种突变激酶的活性，但 AML 中索拉非尼的耐药性很快就会出现，这表明索拉非尼在联合治疗中比单独使用更有效。索拉非尼的另一个关键分子靶点是抗凋亡蛋白 Mcl-1。索拉非尼能够迅速关闭所有研究的血液恶性肿瘤中几乎所有的 Mcl-1，包括 B 慢性淋巴细胞白血病，这是其抗白血病活性以及基于索拉非尼的治疗组合的关键因素。在这方面，特别有趣的是，许多化疗药物或创新的抗肿瘤化合物，如重组 TRAIL 或 MDM2 蛋白抑制剂，要么无法下调 Mcl-1，要么在某些情况下促进 Mcl-1 的反常诱导。在这篇综述中，将讨论 Mcl-1 在介导索拉非尼的抗白血病活性中的作用的不断增加的证据，以及有前途的治疗前景。
