期刊
NATURE MEDICINE
卷 24, 期 4, 页码 497-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4493
关键词
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资金
- Aplastic Anemia and Myelodysplastic Syndromes (MDS) International Foundation
- Lauri Strauss Leukemia Foundation
- Edward P. Evans Foundation
- Taub Foundation
- Department of Defense Bone Marrow Failure Research Program [BM150092, W81XWH-12-1-0041]
- National Institutes of Health National Heart, Lung and Blood Institute [R01 HL128239]
- Josie Robertson Investigator Program
- Starr Foundation [I8-A8-075]
- Leukemia and Lymphoma Society [2314-17]
- Pershing Square Sohn Cancer Research Alliance
- NATIONAL CANCER INSTITUTE [P30CA008748] Funding Source: NIH RePORTER
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.
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