Specific mutations in the D1-D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors.
Specific mutations in the D1-D2 linker region of VCP/p97 enhance ATPase activity and confer resistance to VCP inhibitors.
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DOI：
10.1038/cddiscovery.2017.65
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发表时间：
2017
影响因子：
7
通讯作者：
Chien J
中科院分区：
文献类型：
--
作者：
Bastola P;Wang F;Schaich MA;Gan T;Freudenthal BD;Chou TF;Chien J
Valosin-containing protein（VCP）与几个伴侣蛋白一起从E3连接酶复合物中提取泛素化的客户蛋白，并通过泛素-蛋白酶体系统促进其降解。因此，它在调节蛋白质质量控制和各种细胞途径中起着重要作用。最近的研究还确定VCP是卵巢癌中的谱系特异性必需基因。一种口服生物可利用的VCP抑制剂CB-5083目前正处于I期临床试验中，因为它在多种肿瘤异种移植模型中显示出治疗效果。然而，对CB-5083的耐药机制尚不清楚。在这里，我们表征了对CB-5083的抗性的分子机制。使用CB-5083的增量暴露，我们建立了CB-5083耐药的卵巢癌细胞，与亲本细胞相比，其在体外显示出5至6倍的抗性。VCP编码区的基因组和互补DNA测序揭示了共选择突变的模式：（1）一个拷贝中密码子470处的错义突变导致ATP酶活性增加，（2）另一个拷贝中密码子606或密码子616处的无义或移码突变导致等位基因特异性表达丧失。无偏分子对接研究显示密码子470为CB-5083的推定结合位点。此外，来自癌症基因组图谱（TCGA）的癌症基因组中的体细胞突变的分析表明，密码子616包含VCP中的热点突变。因此，鉴定这些与VCP抑制剂体外耐药相关的突变可能有助于筛选患者参加临床试验时作为潜在的治疗诊断标志物。VCP已经成为几种癌症类型的可行治疗靶点，因此靶向这种过度活跃的VCP突变体应该有助于改善癌症患者的治疗结果。
Valosin-containing protein (VCP), together with several partner proteins, extracts ubiquitinated client proteins from E3 ligase complex and facilitates their degradation through ubiquitin–proteasome system. Therefore, it plays an important role in regulating protein quality control and various cellular pathways. Recent studies also identified VCP as a lineage-specific essential gene in ovarian cancer. An orally bioavailable VCP inhibitor, CB-5083, is currently in Phase I clinical trials because it shows therapeutic effects in multiple tumor xenograft models. However, the mechanism of resistance to CB-5083 is unknown. Here, we characterized molecular mechanism of resistance to CB-5083. Using incremental exposure to CB-5083, we established CB-5083-resistant ovarian cancer cells that showed five- to six-fold resistance in vitro compared with parental cells. Genomic and complementary DNA sequencing of the VCP coding region revealed a pattern of co-selected mutations: (1) missense mutations at codon 470 in one copy resulting in increased ATPase activity and (2) nonsense or frameshift mutations at codon 606 or codon 616 in another copy causing the loss of allele-specific expression. Unbiased molecular docking studies showed codon 470 as a putative binding site for CB-5083. Furthermore, the analysis of somatic mutations in cancer genomes from the Cancer Genome Atlas (TCGA) indicated that codon 616 contains hotspot mutations in VCP. Thus, identification of these mutations associated with in vitro resistance to VCP inhibitors may be useful as potential theranostic markers while screening for patients to enroll in clinical trials. VCP has emerged as a viable therapeutic target for several cancer types, and therefore targeting such hyperactive VCP mutants should aid in improving the therapeutic outcome in cancer patients.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
DOI：
10.1038/nsb972
发表时间：
2003-10-01
期刊：
NATURE STRUCTURAL BIOLOGY
影响因子：
--
作者：
DeLaBarre, B;Brunger, AT
通讯作者：
Brunger, AT
影响因子：
6.6
作者：
Bastola, Prabhakar;Neums, Lisa;Chien, Jeremy
通讯作者：
Chien, Jeremy
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH
影响因子：
3
作者：
Trott, Oleg;Olson, Arthur J.
通讯作者：
Olson, Arthur J.