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 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.

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Acknowledgements

We thank H3 Biomedicine employees for their support in this project. A.Y. was supported by grants from the Aplastic Anemia and Myelodysplastic Syndromes (MDS) International Foundation and the Lauri Strauss Leukemia Foundation. O.A.-W. was supported by grants from the Edward P. Evans Foundation, the Taub Foundation, the Department of Defense Bone Marrow Failure Research Program (BM150092 and W81XWH-12-1-0041), National Institutes of Health National Heart, Lung and Blood Institute (R01 HL128239), the Josie Robertson Investigator Program, an award from the Starr Foundation (I8-A8-075), the Leukemia and Lymphoma Society (2314-17) and the Pershing Square Sohn Cancer Research Alliance.

Author information

Author notes

    • Michael Seiler
    • , Akihide Yoshimi
    •  & Rachel Darman

    These authors contributed equally to this work.

Affiliations

  1. H3 Biomedicine Inc., Cambridge, Massachusetts, USA.

    • Michael Seiler
    • , Rachel Darman
    • , Betty Chan
    • , Gregg Keaney
    • , Michael Thomas
    • , Anant A Agrawal
    • , Benjamin Caleb
    • , Alfredo Csibi
    • , Peter Fekkes
    • , Craig Karr
    • , Linda Lee
    • , Pavan Kumar
    • , Xiang Liu
    • , Crystal Mackenzie
    • , Carol Meeske
    • , Yoshiharu Mizui
    • , Eunice Park
    • , Ermira Pazolli
    • , Shouyong Peng
    • , Sudeep Prajapati
    • , Teng Teng
    • , John Wang
    • , Markus Warmuth
    • , Huilan Yao
    • , Lihua Yu
    • , Ping Zhu
    • , Peter G Smith
    •  & Silvia Buonamici
  2. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Akihide Yoshimi
    • , Stanley Chun-Wei Lee
    • , Justin Taylor
    •  & Omar Abdel-Wahab
  3. Eisai Inc., Andover, Massachusetts, USA.

    • Eckley Sean
    •  & George Lai
  4. Leukemia Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

    • Virginia Klimek
    •  & Omar Abdel-Wahab
  5. Department of Hematologic Malignancies and Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, USA.

    • Eric Padron

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Contributions

G.K., S. Prajapati, J.W., and X.L guided and performed the medicinal chemistry efforts that led to identification of H3B-8800. E. Park, A.A.A., B.C., and P.F. performed the in vitro biochemical assays. A.Y., A.C., B.C., R.D., C.K., L.L., P.K., C. Mackenzie, Y.M., T.T., H.Y., P.Z., P.G.S., and S.B. performed experiments and analyses of H3B-8800 performance in in vitro cellular assays. M.T., E.S., G.L., E. Pazolli, C. Meeske, P.G.S., M.W., and S.B. performed studies and analyzed data from the cell line xenografts. V.K. and E. Padron provided patient materials used for PDX models. A.Y., S.C-W.L., J.T., and O.A.-W. generated PDX models and performed PDX experiments and analyses. M.S., S. Peng, and L.Y. performed RNA-seq analyses. O.A.-W., M.S., A.A.A., P.G.S., and S.B. wrote the manuscript.

Competing interests

M.T., B.C., M.S., A.A.A., B. Chan, B. Caleb, A.C., R.D., P.F., C.K., G.K., L.L., P.K., X.L., C. Mackenzie, C. Meeske, Y.M., E. Park, S. Peng, S. Prajapati, T.T., J.W., M.W., H.Y., L.Y., P.Z., P.G.S. and S.B. are employees of H3 Biomedicine, Inc., and E.S. and G.L. are employees of Eisai, Inc.

Corresponding author

Correspondence to Silvia Buonamici.

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https://doi.org/10.1038/nm.4493

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