Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies
Roles for deregulated receptor tyrosine kinases and their downstream signaling molecules in hematologic malignancies
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DOI：
10.1111/j.1349-7006.2007.00717.x
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发表时间：
2008-03
期刊：
影响因子：
5.7
通讯作者：
I. Matsumura;M. Mizuki;Y. Kanakura
中科院分区：
文献类型：
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作者：
I. Matsumura;M. Mizuki;Y. Kanakura
造血细胞的生长、存活和分化受造血生长因子及其受体相互作用的调控。这些相互作用的缺陷导致造血失败，而这些信号的异常升高和/或持续激活导致血液系统恶性肿瘤。其中，c-Kit、血小板衍生生长因子受体(PDGFR)和Flt3等受体酪氨酸激酶(RTK)的结构性激活突变常参与各种血液系统恶性肿瘤的发病过程。RTK的结构性激活是由多种机制引起的，包括染色体易位和涉及其调控区的各种突变。染色体易位通常产生由RTKs的细胞质结构域和融合伙伴的二聚化或多聚化基序组成的嵌合蛋白，导致RTKs的结构性二聚化。另一方面，调控区域的错义、插入或缺失突变，如膜旁结构域、激活环和胞外区，也主要通过阻止自身抑制调节而导致RTK的结构性激活。致癌RTK可激活RAS/MAPK、PI3-K/Akt/mTOR、STATs等下游信号分子以及配体激活的野生型RTK。然而，它们的信号在数量和质量上都与野生型RTK不同。基于这些发现，已经开发了几种针对致癌RTK或其下游分子的药物：针对RTK本身的伊马替尼和Flt3抑制剂，针对下游信号分子的法尼基转移酶抑制剂，mTOR抑制剂和MEK抑制剂。随着使用这些药物的几项临床试验取得了可喜的结果，这些分子靶向药物的建立是可望的。(癌症科学2008；99：479-485)
Growth, survival and differentiation of hematopoietic cells are regulated by the interactions between hematopoietic growth factors and their receptors. The defect in these interactions results in a failure of hematopoiesis, while aberrantly elevated and/or sustained activation of these signals cause hematologic malignancies. Among them, constitutively activating mutations of the receptor tyrosine kinases (RTKs), such as c‐Kit, platelet‐derived growth factor receptor (PDGFR) and FLT3, are often involved in the pathogenesis of various types of hematologic malignancies. Constitutive activation of RTKs is provoked by several mechanisms including chromosomal translocations and various mutations involving their regulatory regions. Chromosomal translocations commonly generate chimeric proteins consisting of the cytoplasmic domain of RTKs and the dimerization or multimerization motif of the fusion partner, resulting in the constitutive dimerization of RTKs. On the other hand, missense, insertion or deletion mutations in the regulatory regions, such as juxtamembrane domain, activation loop, and extracellular domain, also cause constitutive activation of RTKs mainly by preventing the auto‐inhibitory regulation. Oncogenic RTKs activate downstream signaling molecules such as Ras/MAPK, PI3‐K/Akt/mTOR, and STATs as well as ligand‐activated wild type RTKs. However, their signals are quantitatively and qualitatively different from wild type RTKs. Based on these findings, several agents that target oncogenic RTKs or their downstream molecules have been developed: imatinib and FLT3 inhibitors for RTKs themselves, farnesyltransferase inhibitors, mTOR inhibitors and MEK inhibitors for the downstream signaling molecules. As promising results have been obtained in several clinical trials using these agents, the establishment of these molecular targeted agents is expected. (Cancer Sci 2008; 99: 479–485)