Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy.
Targeting the MAPK-RAS-RAF signaling pathway in cancer therapy.
复制标题
癌症治疗中靶向 MAPK-RAS-RAF 信号通路。
DOI：
10.1517/14728222.2011.645805
复制
发表时间：
2012-01
影响因子：
5.8
通讯作者：
El-Naggar AK
中科院分区：
文献类型：
--
作者：
Santarpia L;Lippman SM;El-Naggar AK
丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）信号通路是一条重要的信号转导通路，在肿瘤发生过程中起重要作用。这些活化的激酶传递细胞外信号，调节细胞生长、分化、增殖、凋亡和迁移功能。RAS-RAF-MEK-ERK-MAPK（RAS-MAPK）通路的改变在人类癌症中经常被报道，这是由于受体酪氨酸激酶的异常激活或主要在RAS或RAF基因中的功能获得性突变。因此，这些途径被认为是癌症治疗的潜在治疗靶点。最近，已经开发了几种针对该途径的小分子抑制剂，目前正在临床试验中进行测试。本文重点介绍了RAS-MAPK通路的生物学作用，其失调的后果，以及小分子抑制剂的发展。本文将沿着对靶向RAS-MAPK通路的基本原理进行综述，并讨论各种抑制分子作为抗癌药物在临床试验中的应用和结果。RAS-MAPK通路介导细胞对生长信号的反应，并且在人类癌症中经常被解除调节。RAS和BRAF基因中的激活突变已在广泛的癌症中被频繁鉴定。MEK和特别是RAF激酶的抑制剂在临床试验中是有效的，副作用可控。需要分析RAS和BRAF基因的突变，作为对治疗反应的标志物，以避免矛盾效应。RAS-MAPK分子机制在恶性细胞中的调节或对RAF抑制剂的获得性耐药性的基础的进一步表征将促进新的联合治疗的开发。
The mitogen-activated protein kinase (MAPK) pathway comprises several key signaling components and phosphorylation events that play important role in tumorigenesis. These activated kinases transmit extracellular signals that regulate cell growth, differentiation, proliferation, apoptosis and migration functions. Alteration of the RAS-RAF-MEK-ERK-MAPK (RAS-MAPK) pathway has frequently been reported in human cancer as a result of abnormal activation of receptor tyrosine kinases or gain-of-function mutations mainly in the RAS or RAF genes. Accordingly, these pathways are considered a potential therapeutic target for cancer treatment. Recently, several small-molecule inhibitors targeting this pathway have been developed and are currently being tested in clinical trials. This paper focuses on the biological role of the RAS-MAPK pathway, the consequence of its disregulation, and the development of small-molecule inhibitors. The rationale for targeting the RAS-MAPK pathway will be reviewed here along with a discussion of the application and the results of various inhibitory molecules as anticancer agents in clinical trials. The RAS-MAPK pathway mediates cellular responses to growth signals and is often deregulated in human cancer. Activating mutations in the RAS and BRAF genes have been frequently identified in a wide range of cancers. Inhibitors of MEK and particularly of RAF kinases, have been effective in clinical trials with manageable side effects. RAS and BRAF genes need to be analyzed for mutations as markers of response to treatments and to avoid paradoxical effects. Further characterization of the RAS-MAPK molecular mechanisms regulation in malignant cells or underlying the acquired resistance to RAF inhibitors will facilitate development of novel combination therapies.
登录
查看更多内容
影响因子：
5.7
作者：
Davies, Barry R.;Logie, Armelle;Smith, Paul D.
通讯作者：
Smith, Paul D.
影响因子：
64.8
作者：
BINETRUY, B;SMEAL, T;KARIN, M
通讯作者：
KARIN, M
影响因子：
5.7
作者：
Daouti, Sherif;Higgins, Brian;Niu, Huifeng
通讯作者：
Niu, Huifeng
影响因子：
14.9
作者：
Diez, Diego;Sanchez-Jimenez, Francisca;Ranea, Juan A. G.
通讯作者：
Ranea, Juan A. G.
影响因子：
8
作者：
Gazdar, A. F.
通讯作者：
Gazdar, A. F.