H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers

被引：385

作者：

Seiler, Michael ^{[1
]}

Yoshimi, Akihide ^{[2
]}

Darman, Rachel ^{[1
]}

Chan, Betty ^{[1
]}

Keaney, Gregg ^{[1
]}

Thomas, Michael ^{[1
]}

Agrawal, Anant A. ^{[1
]}

Caleb, Benjamin ^{[1
]}

Csibi, Alfredo ^{[1
]}

Sean, Eckley ^{[3
]}

Fekkes, Peter ^{[1
]}

Karr, Craig ^{[1
]}

Klimek, Virginia ^{[4
]}

Lai, George ^{[3
]}

Lee, Linda ^{[1
]}

Kumar, Pavan ^{[1
]}

Lee, Stanley Chun-Wei ^{[2
]}

Liu, Xiang ^{[1
]}

Mackenzie, Crystal ^{[1
]}

Meeske, Carol ^{[1
]}

Mizui, Yoshiharu ^{[1
]}

Padron, Eric ^{[5
]}

Park, Eunice ^{[1
]}

Pazolli, Ermira ^{[1
]}

Peng, Shouyong ^{[1
]}

Prajapati, Sudeep ^{[1
]}

Taylor, Justin ^{[2
]}

Teng, Teng ^{[1
]}

Wang, John ^{[1
]}

Warmuth, Markus ^{[1
]}

Yao, Huilan ^{[1
]}

Yu, Lihua ^{[1
]}

Zhu, Ping ^{[1
]}

Abdel-Wahab, Omar ^{[2
,4
]}

Smith, Peter G. ^{[1
]}

Buonamici, Silvia ^{[1
]}

机构：

[1] H3 Biomed Inc, Cambridge, MA 02139 USA

[2] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10021 USA

[3] Eisai Inc, Andover, MA USA

[4] Mem Sloan Kettering Canc Ctr, Dept Med, Leukemia Serv, New York, NY 10021 USA

[5] H Lee Moffitt Canc Ctr & Res Inst, Dept Hematol Malignancies & Immunol Program, Tampa, FL USA

来源：

NATURE MEDICINE | 2018年 / 24卷 / 04期

基金：

美国国家卫生研究院;

关键词：

MUTATIONS; SF3B1; RECOGNITION; MYELODYSPLASIA; EXPRESSION; SELECTION; DATABASE; REVEALS; CAPTURE; PRODUCT;

D O I：

10.1038/nm.4493

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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(1-6). Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function(7-11), 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.

引用

页码：497 / +

页数：15

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