H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers.
H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers.
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DOI：
10.1038/nm.4493
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发表时间：
2018-05
期刊：
影响因子：
82.9
通讯作者：
Buonamici S
中科院分区：
文献类型：
--
作者：
Seiler M;Yoshimi A;Darman R;Chan B;Keaney G;Thomas M;Agrawal AA;Caleb B;Csibi A;Sean E;Fekkes P;Karr C;Klimek V;Lai G;Lee L;Kumar P;Lee SC;Liu X;Mackenzie C;Meeske C;Mizui Y;Padron E;Park E;Pazolli E;Peng S;Prajapati S;Taylor J;Teng T;Wang J;Warmuth M;Yao H;Yu L;Zhu P;Abdel-Wahab O;Smith PG;Buonamici S
癌症的基因组分析已经确定了RNA剪接因子编码基因SF3B1， U2AF1和SRSF2的复发点突变，这些突变赋予功能改变。携带这些突变的癌细胞优先依赖于野生型（WT）剪接体的功能，但临床相关的治疗方法目前还不存在。在这里，我们描述了一种口服的SF3b复合物调节剂H3B-8800，它能有效和优先地杀死剪接体突变的上皮和血液肿瘤细胞。H3B-8800的这些杀伤作用是由于其与SF3b复合物的直接相互作用，在编码SF3b成分的基因突变的耐药细胞中，H3B-8800的活性丧失就证明了这一点。虽然H3B-8800调节WT和突变剪接体的活性，但剪接体突变细胞的优先杀伤是由于保留了短的富含gc的内含子，这些内含子富含编码剪接体成分的基因。这些数据证明了剪接调节在剪接体突变癌症中的治疗潜力。
Genomic analyses of cancer have identified recurrent point mutations in the RNA splicing factor–encoding genes SF3B1, U2AF1, and SRSF2 that confer an alteration of function. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function, but clinically relevant means to therapeutically target the spliceosome do not currently exist. Here we describe an orally available modulator of the SF3b complex, H3B-8800, which potently and preferentially kills spliceosome-mutant epithelial and hematologic tumor cells. These killing effects of H3B-8800 are due to its direct interaction with the SF3b complex, as evidenced by loss of H3B-8800 activity in drug-resistant cells bearing mutations in genes encoding SF3b components. Although H3B-8800 modulates WT and mutant spliceosome activity, the preferential killing of spliceosome-mutant cells is due to retention of short, GC-rich introns, which are enriched for genes encoding spliceosome components. These data demonstrate the therapeutic potential of splicing modulation in spliceosome-mutant cancers.
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影响因子：
30.8
作者：
Harbour, J. William;Roberson, Elisha D. O.;Anbunathan, Hima;Onken, Michael D.;Worley, Lori A.;Bowcock, Anne M.
通讯作者：
Bowcock, Anne M.
影响因子：
16
作者：
Hegele, Anna;Kamburov, Atanas;Stelzl, Ulrich
通讯作者：
Stelzl, Ulrich
影响因子：
8.8
作者：
Darman, Rachel B.;Seiler, Michael;Buonamici, Silvia
通讯作者：
Buonamici, Silvia
影响因子：
50.3
作者：
Obeng EA;Chappell RJ;Seiler M;Chen MC;Campagna DR;Schmidt PJ;Schneider RK;Lord AM;Wang L;Gambe RG;McConkey ME;Ali AM;Raza A;Yu L;Buonamici S;Smith PG;Mullally A;Wu CJ;Fleming MD;Ebert BL
通讯作者：
Ebert BL
影响因子：
64.5
作者：
Ciriello G;Gatza ML;Beck AH;Wilkerson MD;Rhie SK;Pastore A;Zhang H;McLellan M;Yau C;Kandoth C;Bowlby R;Shen H;Hayat S;Fieldhouse R;Lester SC;Tse GM;Factor RE;Collins LC;Allison KH;Chen YY;Jensen K;Johnson NB;Oesterreich S;Mills GB;Cherniack AD;Robertson G;Benz C;Sander C;Laird PW;Hoadley KA;King TA;TCGA Research Network;Perou CM
通讯作者：
Perou CM