| Literature DB >> 29457796 |
Michael Seiler1, Akihide Yoshimi2, Rachel Darman1, Betty Chan1, Gregg Keaney1, Michael Thomas1, Anant A Agrawal1, Benjamin Caleb1, Alfredo Csibi1, Eckley Sean3, Peter Fekkes1, Craig Karr1, Virginia Klimek4, George Lai3, Linda Lee1, Pavan Kumar1, Stanley Chun-Wei Lee2, Xiang Liu1, Crystal Mackenzie1, Carol Meeske1, Yoshiharu Mizui1, Eric Padron5, Eunice Park1, Ermira Pazolli1, Shouyong Peng1, Sudeep Prajapati1, Justin Taylor2, Teng Teng1, John Wang1, Markus Warmuth1, Huilan Yao1, Lihua Yu1, Ping Zhu1, Omar Abdel-Wahab2,4, Peter G Smith1, Silvia Buonamici1.
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.Entities:
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Year: 2018 PMID： 29457796 PMCID： PMC6730556 DOI： 10.1038/nm.4493
Source DB: PubMed Journal: Nat Med ISSN： 1078-8956 Impact factor: 53.440