Activation of abl family kinases in solid tumors.
Activation of abl family kinases in solid tumors.
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DOI：
10.1177/1947601912458586
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发表时间：
2012-05-01
期刊：
影响因子：
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通讯作者：
Plattner, Rina
中科院分区：
文献类型：
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作者：
Ganguly, Sourik S;Plattner, Rina
虽然c-Abl和Arg非受体酪氨酸激酶是众所周知的驱动白血病的发展，其在实体瘤中的作用一直没有得到重视，直到最近。越来越多的证据表明，c-Abl和/或Arg在一些实体瘤细胞系中通过不涉及基因突变/易位的独特机制被激活，并且c-Abl/Arg激活促进基质降解、侵袭、增殖、肿瘤发生和/或转移，这取决于肿瘤类型。然而，一些数据表明，c-Abl也可以抑制某些细胞环境中的侵袭、增殖和肿瘤发生。因此，c-Abl/Arg可以作为分子开关，其响应于一些刺激（例如，肝配蛋白）或当无活性/受调节时，或当响应于其它信号而促进侵袭和增殖时（例如，活化的生长因子受体，抑制剂表达的丧失），其诱导持续的活化。显然，需要更多的数据来确定c-Abl/Arg激活在原发性肿瘤和进展过程中的程度和患病率，并且需要额外的动物研究来证实体外结果。此外，c-Abl/Arg抑制剂已用于许多实体瘤临床试验;然而，这些试验均不限于肿瘤表达高度活化的c-Abl/Arg的患者（靶向试验）。靶向试验对于确定c-Abl/Arg抑制剂是否可以成为肿瘤由c-Abl/Arg驱动的患者的有效治疗选择至关重要。
Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.