Targeting Rac and Cdc42 GTPases in Cancer.
Targeting Rac and Cdc42 GTPases in Cancer.
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DOI：
10.1158/0008-5472.can-18-0619
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发表时间：
2018-06-15
期刊：
影响因子：
11.2
通讯作者：
Dharmawardhane S
中科院分区：
文献类型：
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作者：
Maldonado MDM;Dharmawardhane S
Rac 和 Cdc42 是小 GTP 酶，与多种人类癌症有关，并参与上皮间质转化、细胞周期进展、迁移/侵袭、肿瘤生长、血管生成和致癌转化。除了黑色素瘤中的 P29S 驱动突变外，Rac 和 Cdc42 在癌症中通常不会突变，但会过度表达（基因扩增和 mRNA 上调）或过度激活。 Rac 和 Cdc42 通过致癌细胞表面受体（例如生长因子受体）的信号传导而被过度激活，这些受体聚集在调节其 GDP/GTP 交换的鸟嘌呤核苷酸交换因子 (GEF) 上。因此，针对 Rac 和 Cdc42 代表了一种有前途的精确癌症治疗策略，以及抑制旁路信号传导，从而促进对细胞表面受体靶向治疗的耐药性。因此，了解这些关键信号中间体的调节机制是开发有效抑制剂的关键。在这篇综述中，我们重点关注Rac和Cdc42在癌症中的作用，并总结了Rac和Cdc42靶向药物的调控机制、抑制功效和抗癌潜力。
Rac and Cdc42 are small GTPases that have been linked to multiple human cancers, and implicated in epithelial to mesenchymal transition, cell cycle progression, migration/invasion, tumor growth, angiogenesis, and oncogenic transformation. With the exception of the P29S driver mutation in melanoma, Rac and Cdc42 are not generally mutated in cancer, but are overexpressed (gene amplification and mRNA upregulation) or hyperactivated. Rac and Cdc42 are hyperactivated via signaling through oncogenic cell surface receptors, such as growth factor receptors, which converge on the guanine nucleotide exchange factors (GEFs) that regulate their GDP/GTP exchange. Hence, targeting Rac and Cdc42 represent a promising strategy for precise cancer therapy, as well as for inhibition of bypass signaling that promotes resistance to cell surface receptor-targeted therapies. Therefore, an understanding of the regulatory mechanisms of these pivotal signaling intermediates is key for the development of effective inhibitors. In this review, we focus on the role of Rac and Cdc42 in cancer and summarize the regulatory mechanisms, inhibitory efficacy, and the anticancer potential of Rac and Cdc42 targeting agents.