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

   


Authors: Seiler, M.; Yoshimi, A.; Darman, R.; Chan, B.; Keaney, G.; Thomas, M.; Agrawal, A. A.; Caleb, B.; Csibi, A.; Sean, E.; Fekkes, P.; Karr, C.; Klimek, V.; Lai, G.; Lee, L.; Kumar, P.; Lee, S. C. W.; 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, P. G.; Buonamici, S.
Article Title: H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers
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. © 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
Journal Title: Nature Medicine
Volume: 24
Issue: 4
ISSN: 1078-8956
Publisher: Nature Publishing Group  
Date Published: 2018-04-01
Start Page: 497
End Page: 504
Language: English
DOI: 10.1038/nm.4493
PROVIDER: scopus
PUBMED: 29457796
PMCID: PMC6730556
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85044272325&doi=10.1038%2fnm.4493&partnerID=40&md5=9b5aab3f365c16d7b82a75f3a62f6730
Notes: Article -- Export Date: 1 May 2018 -- Source: Scopus
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MSK Authors
  1. Virginia Klimek
    147 Klimek
  2. Omar Ibrahim Abdel-Wahab
    573 Abdel-Wahab
  3. Stanley Chun-Wei Lee
    43 Lee
  4. Akihide Yoshimi
    35 Yoshimi
  5. Justin Taylor
    51 Taylor
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