論文 - 詳細
| RRC ID | 52611 |
|---|---|
| 著者 | 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. |
| タイトル | H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers. |
| ジャーナル | Nat Med |
| Abstract |
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. |
| 巻・号 | 24(4) |
| ページ | 497-504 |
| 公開日 | 2018-5-1 |
| DOI | 10.1038/nm.4493 |
| PII | nm.4493 |
| PMID | 29457796 |
| PMC | PMC6730556 |
| MeSH | Administration, Oral Animals Base Sequence Humans Introns / genetics K562 Cells Leukemia / genetics Leukemia / pathology Mice Mutation Neoplasms / drug therapy* Neoplasms / genetics* Neoplasms / pathology Piperazines / administration & dosage Piperazines / pharmacology* Pyridines / administration & dosage Pyridines / pharmacology* RNA Splicing / drug effects RNA Splicing / genetics* RNA, Messenger / genetics RNA, Messenger / metabolism Small Molecule Libraries / pharmacology Small Molecule Libraries / therapeutic use* Spliceosomes / genetics* Tumor Burden Xenograft Model Antitumor Assays |
| IF | 36.13 |
| 引用数 | 108 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 152 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HCT116(RCB2979) |