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Therapeutic targeting of splicing in cancer

Nature Medicine volume 22, pages 976–986 (2016)Cite this article

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Abstract

Recent studies have highlighted that splicing patterns are frequently altered in cancer and that mutations in genes encoding spliceosomal proteins, as well as mutations affecting the splicing of key cancer-associated genes, are enriched in cancer. In parallel, there is also accumulating evidence that several molecular subtypes of cancer are highly dependent on splicing function for cell survival. These findings have resulted in a growing interest in targeting splicing catalysis, splicing regulatory proteins, and/or specific key altered splicing events in the treatment of cancer. Here we present strategies that exist and that are in development to target altered dependency on the spliceosome, as well as aberrant splicing, in cancer. These include drugs to target global splicing in cancer subtypes that are preferentially dependent on wild-type splicing for survival, methods to alter post-translational modifications of splicing-regulating proteins, and strategies to modulate pathologic splicing events and protein–RNA interactions in cancer.

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Figure 1: Diverse mechanisms by which alterations in splicing promote cancer and treatment resistance.
Figure 2: Methods by which splicing may be modulated for cancer therapy.
Figure 3: Pharmacologic methods to disrupt core spliceosome function.

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Acknowledgements

S.C.-W.L. is supported by a Leukemia and Lymphoma Society (LLS) Special Fellow Award. O.A.-W. is supported by grants from the Edward P. Evans Foundation, the Department of Defense Bone Marrow Failure Research Program (BM150092 and W81XWH-12-1-0041), the US National Institutes of Health (NIH)–NHLBI (R01 HL128239), the Josie Robertson Investigator Program, the Mr. William H. Goodwin and Mrs. Alice Goodwin Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of MSKCC and the Pershing Square Sohn Cancer Research Alliance, as well as by an NIH K08 Clinical Investigator Award (1K08CA160647-01), a Damon Runyon Clinical Investigator Award and an award from the Starr Foundation (I8-A8-075).

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Authors and Affiliations

  1. Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, New York, USA

    Stanley Chun-Wei Lee & Omar Abdel-Wahab

  2. Department of Medicine, Leukemia Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA

    Omar Abdel-Wahab

Authors
  1. Stanley Chun-Wei Lee
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  2. Omar Abdel-Wahab
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Corresponding author

Correspondence to Omar Abdel-Wahab.

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Competing interests

O.A.-W. receives funding support from H3 Biomedicine Inc.

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Lee, SW., Abdel-Wahab, O. Therapeutic targeting of splicing in cancer. Nat Med 22, 976–986 (2016). https://doi.org/10.1038/nm.4165

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