Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
Oncogenic BRAF Deletions That Function as Homodimers and Are Sensitive to Inhibition by RAF Dimer Inhibitor LY3009120
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DOI：
10.1158/2159-8290.cd-15-0896
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发表时间：
2016-03-01
期刊：
影响因子：
28.2
通讯作者：
Peng, Sheng-Bin
中科院分区：
文献类型：
--
作者：
Chen, Shih-Hsun;Zhang, Youyan;Peng, Sheng-Bin
我们已经在胰腺癌、肺癌、卵巢癌和甲状腺癌中发现了先前未发现的BRAF框内缺失，这些缺失位于激活域的αC-螺旋区域附近。这些缺失与KRAS突变是互斥的，并发生在4.21%的KRAS野生型胰腺癌中。在含有BRAF缺失的细胞中的siRNA敲除表明，MAPK活性和细胞生长是BRAF依赖的。在结构上，BRAF的缺失被预测会缩短β3/αC-螺旋环，并通过将螺旋锁定在有利于二聚体形成的活跃的αC-螺旋构象中而阻碍其灵活性。表达1485-P490缺失的BRAF能够以BRAF二聚体依赖的方式转化NIH/3T3细胞。在BRAF缺失细胞中，BRAF同源二聚体是主要的RAF二聚体，对BRAF抑制剂维莫拉非尼耐药，对RAF二聚体抑制剂LY3009120敏感。在BRAF缺失的肿瘤模型中，LY3009120表现出肿瘤生长减退，而维莫拉非尼则表现为不活跃。标志：本研究发现了致癌的BRAF缺失，其激活机制明显依赖于肿瘤细胞中BRAF二聚体的形成。LY3009120对这些细胞具有活性，是具有这些BRAF缺失或BRAF作为二聚体功能的其他非典型BRAF突变的癌症患者的潜在治疗选择。(C)2016年AACR。
We have identified previously undiscovered BRAF in-frame deletions near the alpha C-helix region of the kinase domain in pancreatic, lung, ovarian, and thyroid cancers. These deletions are mutually exclusive with KRAS mutations and occur in 4.21% of KRAS wild-type pancreatic cancer. siRNA knockdown in cells harboring BRAF deletions showed that the MAPK activity and cell growth are BRAF dependent. Structurally, the BRAF deletions are predicted to shorten the beta 3/alpha C-helix loop and hinder its flexibility by locking the helix in the active alpha C-helix-in conformation that favors dimer formation. Expression of L485-P490-deleted BRAF is able to transform NIH/3T3 cells in a BRAF dimer-dependent manner. BRAF homodimer is confirmed to be the dominant RAF dimer by proximity ligation assays in BRAF deletion cells, which are resistant to the BRAF inhibitor vemurafenib and sensitive to LY3009120, a RAF dimer inhibitor. In tumor models with BRAF deletions, LY3009120 has shown tumor growth regression, whereas vemurafenib is inactive.SIGNIFICANCE: This study discovered oncogenic BRAF deletions with a distinct activation mechanism dependent on the BRAF dimer formation in tumor cells. LY3009120 is active against these cells and represents a potential treatment option for patients with cancer with these BRAF deletions, or other atypical BRAF mutations where BRAF functions as a dimer. (C) 2016 AACR.