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
リソース情報
ヒト・動物細胞 HCT116(RCB2979)