Department of Clinical and Biological Sciences, University of Turin, Turin, Italy.
Clin Cancer Res. 2012 Feb 15;18(4):930-7. doi: 10.1158/1078-0432.CCR-10-1613. Epub 2011 Dec 8.
Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies. Here, we summarize the molecular pathways that are abnormally activated by the oncoprotein. Such pathways may provide additional opportunities to develop new drugs to overcome the resistance to tyrosine kinase inhibitors. In particular, the phosphoinositide 3-kinase (PI3K)/AKT pathway can be effectively blocked by mTOR inhibitors, and several compounds can hit the RAS pathway and the resulting mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) and MAP kinase activation. Furthermore, mitotic kinases can be blocked by Aurora kinase inhibitors, and Pim kinases can be blocked by selective serine-threonine kinase inhibitors. Finally, the abnormal pathways that sustain the self-renewal of leukemic stem cells are described as possible targets to completely eradicate leukemic clones. Such pathways include the Hedgehog pathway, which can be blocked by Smoothened inhibitors, and the CXCR4/SDF1 axis, which can be targeted by specific antagonists.
异常的酪氨酸激酶活性在许多血液系统疾病中起着关键作用，包括慢性髓性白血病，其特征是 BCR-ABL 的组成性活性。因此，ABL 代表了新治疗策略的重要靶点。在这里，我们总结了致癌蛋白异常激活的分子途径。这些途径可能为开发新药物提供更多机会，以克服对酪氨酸激酶抑制剂的耐药性。特别是，磷酸肌醇 3-激酶（PI3K）/AKT 途径可以被 mTOR 抑制剂有效阻断，并且几种化合物可以靶向 RAS 途径以及由此产生的有丝分裂原激活的蛋白（MAP）细胞外信号调节激酶（ERK）1/2（MEK）和 MAP 激酶激活。此外，有丝分裂激酶可以被 Aurora 激酶抑制剂阻断，而 Pim 激酶可以被选择性丝氨酸-苏氨酸激酶抑制剂阻断。最后，描述了维持白血病干细胞自我更新的异常途径，作为彻底根除白血病克隆的可能靶点。这些途径包括 Hedgehog 途径，它可以被 Smoothened 抑制剂阻断，以及 CXCR4/SDF1 轴，它可以被特定的拮抗剂靶向。
