Targeting oncogenic Raf protein-serine/threonine kinases in human cancers

被引:155
作者
Roskoski, Robert, Jr. [1 ]
机构
[1] Blue Ridge Inst Med Res, 3754 Brevard Rd,Suite 116,Box 19, Horse Shoe, NC 28742 USA
关键词
Catalytic spine; K/E/D/D; Melanoma; Protein kinase inhibitor classification; Protein kinase structure; Targeted cancer therapy; TYROSINE KINASE; ANTITUMOR-ACTIVITY; CATALYTIC SUBUNIT; IMPROVED SURVIVAL; BRAF MUTATIONS; PHASE-II; INHIBITORS; ACTIVATION; MELANOMA; MECHANISM;
D O I
10.1016/j.phrs.2018.08.013
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The Ras-Raf-MEK-ERK signal transduction cascade is arguably the most important oncogenic pathway in human cancers. Ras-GTP promotes the formation of active homodimers or heterodimers of A-Raf, B-Raf, and C-Raf by an intricate process. These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2. The latter catalyze the regulatory phosphorylation of dozens of cytosolic and nuclear proteins. The X-ray crystal structure of B-Raf-MEK1 depicts a face-to-face dimer with interacting activation segments; B-Raf is in an active conformation and MEK1 is in an inactive conformation. Besides the four traditional components in the Ras-RafMEK-ERK signaling module, scaffolding proteins such as Kinase Suppressor of Ras (KSR1/2) play an important role in this signaling cascade by functioning as a scaffold protein. RAS mutations occur in about 30% of all human cancers. Moreover, BRAF(v600E) mutations occur in about 8% of all cancers making this the most prevalent oncogenic protein kinase. Vemurafenib and dabrafenib are B-Raf(v600E) inhibitors that were approved for the treatment of melanomas bearing the V600E mutation. Coupling MEK1/2 inhibitors with B-Raf inhibitors is more effective in treating such melanomas and dual therapy is now the standard of care. Vemurafenib and cobimetanib, dabrafenib and trametinib, and encorafenib plus binimetinib are the FDA-approved combinations for the treatment of BRAF(v600E) melanomas. Although such mutations occur in other neoplasms including thyroid, colorectal, and non-small cell lung cancers, these agents are not as effective in treating these non-melanoma neoplasms. Vemurafenib and dabrafenib produce the paradoxical activation of the MAP kinase pathway in wild type BRAF cells. The precise mechanism for this activation is unclear, but drug-induced Raf activating side-to side dimerization appears to be an essential step. Although 63%-76% of all people with advanced melanoma with the BRAF V6ME mutation derive clinical benefit from combination therapy, median progression-free survival lasts only about nine months and 90% of patients develop resistance within one year. The various secondary resistance mechanisms include NRAS or KRAS mutations (20%), BRAF splice variants (16%), BRAF(v600E/K) amplifications (13%), MEK1/2 mutations (7%), and non-MAP kinase pathway alterations (11%). Vemurafenib and dabrafenib bind to an inactive form of B-Raf (aC-helix(out) and DFG-D-in) and are classified as type I1/2 inhibitors. LY3009120 and lifirafenib, which are in the early drug-development stage, bind to a different inactive form of BRaf (DFG-D-out) and are classified as type II inhibitors. Besides targeting B-Raf and MEK protein kinases, immunotherapies that include ipilimumab, pembrolizumab, and nivolumab have been FDA-approved for the treatment of melanomas. Current clinical trials are underway to determine the optimal usage of targeted and immunotherapies.
引用
收藏
页码:239 / 258
页数:20
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