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Clin Cancer Res:难治性黑素瘤新的分子靶标

来源:生物谷 2014-01-01 20:59

2013年12月31日讯 /生物谷BIOON/--根据最近发表在美国癌症研究协会Clinical Cancer Research杂志上的一项研究,科学家确定了黑色素瘤中两个新的BRAF融合,并且存在这些融合的黑色素瘤对抗癌药物MEK抑制剂敏感。据研究人员Sosman博士解释,截至现在,大约35%的黑色素瘤缺乏任何已知的驱动突变基因如BRAF,NRAS,KIT,GNAQ和GNA11。

Sosman博士解释说,研究人员一直有兴趣分析没有这些突变的肿瘤患者,看看他们的肿瘤是否存在有针对性的治疗靶标。在一些癌症中,两个或更多个基因错误融合产生异常蛋白,基因错误融合充当癌症 “驱动器”的功能。

利用靶向性新一代测序分析技术,约8%的不存在上述基因突变的黑色素瘤有BRAF基因的融合,Sosman说,我们的研究结果非常重要,因为他们显然提示,可能还有其他的,身份不明的分子变化,使这些黑色素瘤容易受到现在药物的作用。

利用一个不存在上述基因突变的黑色素患者样本,Sosman及Pao和他们的同事发现了两个基因之间的融合,即PAPSS1和BRAF,他们称之为PAPSS1 -BRAF。然后,他们评价额外的51名患者,其中24名不存在上述基因突变。在这24位患者中有一位,他们发现存在第二个新的BRAF融合,称为TRIM24 -BRAF。

研究人员在实验室中进行了进一步研究,发现发现的两个BRAF基因融合激活MAPK信号通路。然后,他们用BRAF抑制剂维罗非尼(Vemurafenib)或Trametinib处理这些细胞融合,Trametinib是一种抑制MAPK信号通路中蛋白​​MEK的药物。

他们发现,BRAF融合诱导的信号不响应维罗非尼,但Trametinib可以抑制BRAF融合诱导的信号,这表明,他们发现的这种新融合可以使黑色素瘤对MEK抑制剂敏感。

癌症的主要目标是加快有效的治疗方法发展,以帮助病人。研究人员表示:确定新的基因突变有助于确定可能对现有或未来药物疗法敏感是新靶标。(生物谷Bioon.com)

 

BRAF Fusions Define a Distinct Molecular Subset of Melanomas with Potential Sensitivity to MEK Inhibition

Katherine E. Hutchinson,et al.

Purpose: Recurrent “driver” mutations at specific loci in BRAF, NRAS, KIT, GNAQ, and GNA11 define clinically relevant molecular subsets of melanoma, but more than 30% are “pan-negative” for these recurrent mutations. We sought to identify additional potential drivers in “pan-negative” melanoma.

Experimental Design: Using a targeted next-generation sequencing (NGS) assay (FoundationOne) and targeted RNA sequencing, we identified a novel PAPSS1-BRAF fusion in a “pan-negative” melanoma. We then analyzed NGS data from 51 additional melanomas genotyped by FoundationOne, as well as melanoma RNA, whole-genome and whole-exome sequencing data in The Cancer Genome Atlas (TCGA), to determine the potential frequency of BRAF fusions in melanoma. We characterized the signaling properties of confirmed molecular alterations by ectopic expression of engineered cDNAs in 293H cells.

Results: Activation of the mitogen-activated protein kinase (MAPK) pathway in cells by ectopic expression of PAPSS1-BRAF was abrogated by mitogen-activated protein kinase kinase (MEK) inhibition but not by BRAF inhibition. NGS data analysis of 51 additional melanomas revealed a second BRAF fusion (TRIM24-BRAF) in a “pan-negative” sample; MAPK signaling induced by TRIM24-BRAF was also MEK inhibitor sensitive. Through mining TCGA skin cutaneous melanoma dataset, we further identified two potential BRAF fusions in another 49 “pan-negative” cases.

Conclusions: BRAF fusions define a new molecular subset of melanoma, potentially comprising 4% to 8% of “pan-negative” cases. Their presence may explain an unexpected clinical response to MEK inhibitor therapy or assist in selecting patients for MEK-directed therapy.

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