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

2018; Nature Portfolio; Volume: 24; Issue: 4 Linguagem: Inglês

10.1038/nm.4493

1546-170X

Michael Seiler, Akihide Yoshimi, Rachel Darman, Betty Chan, Gregg F. Keaney, Michaël Thomas, Anant A. Agrawal, Benjamin Caleb, Alfredo Csibi, E. Egan Sean, Peter Fekkes, Craig Karr, Virginia M. Klimek, George Lai, Linda Lee, Pavan Kumar, Stanley Chun-Wei Lee, Xiang Liu, Crystal MacKenzie, Carol Meeske, Yoshiharu Mizui, Eric Padron, Eunice Park, Ermira Pazolli, Shouyong Peng, Sudeep Prajapati, Justin Taylor, Teng Teng, John Wang, Markus Warmuth, Huilan Yao, Lihua Yu, Ping Zhu, Omar Abdel‐Wahab, Peter G. Smith, Silvia Buonamici,

RNA and protein synthesis mechanisms

The small molecule H3B-8800 selectively modulates RNA splicing to preferentially kill tumor cells bearing mutations in genes encoding spliceosome components. 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.