H3B-8800, an orally available small-molecule splicing modulator, induces lethality in spliceosome-mutant cancers
Menée in vitro et à l'aide de xénogreffes dérivées de cellules cancéreuses de patients, cette étude montre que H3B-8800, une molécule administrable par voie orale et pouvant moduler l'expression du facteur d'épissage SF3b, induit la mort des cellules cancéreuses présentant des mutations de gènes codant pour des composants de ce facteur
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 function1,2,3,4,5,6. Cancer cells bearing these mutations are preferentially dependent on wild-type (WT) spliceosome function7,8,9,10,11, 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.