Cooperation of BRAFF595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling
Cooperation of BRAFF595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling
复制标题
DOI：
10.1038/leu.2015.319
复制
发表时间：
2016-04-01
期刊：
影响因子：
11.4
通讯作者：
Froehling, S.
中科院分区：
文献类型：
--
作者：
Kordes, M.;Roering, M.;Froehling, S.
激活BRAF突变，特别是V600 E/K，驱动许多癌症，并被认为与突变型RAS相互排斥，而D（594）F（595）G（596）基序中的失活BRAF突变通过矛盾的MEK/ERK激活与RAS合作。由于越来越多地使用全面的肿瘤基因组分析，许多非V600 BRAF突变被检测到，其功能后果和治疗作用往往是未知的。我们研究了一种非典型BRAF突变F595 L，它与组织细胞肉瘤中的突变型HRAS一起沿着，也发生在上皮癌、黑色素瘤和神经母细胞瘤中，并确定了它与突变型RAS的相互作用。与其他DFG基序突变体不同，BRAF（F595 L）是一种具有中间活性的功能获得性变体，其作用并不矛盾，但仍与突变型RAS合作促进致癌信号传导，其被pan-RAF和MEK抑制剂有效阻断。来自患者和细胞系的突变数据显示，BRAF（F595 L）以及其他中等活性的BRAF突变，经常与各种癌症中的突变RAS相一致。这些数据定义了一类独特的激活BRAF突变，扩展了全身性组织细胞病和其他恶性肿瘤患者的范围，这些患者是RAF-MEK-ERK通路治疗阻断的候选人，并强调了全面基因组检测对揭示个体肿瘤脆弱性的价值。
Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.