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Therapeutic targeting of splicing in cancer

Stanley Chun-Wei Lee¹, Omar Abdel-Wahab^1,2

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

Nature Medicine

|September 8, 2016

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.

Insights

Altered splicing is common in cancer, with some cancer types depending on normal splicing for survival. New strategies target spliceosome function and aberrant splicing for cancer treatment.

Area of Science:

Molecular Biology
Cancer Research
Drug Development

Background:

Splicing patterns are frequently altered in cancer.
Mutations in spliceosomal proteins and key cancer genes are enriched in cancer.
Certain cancer subtypes rely heavily on splicing for survival.

Purpose of the Study:

To review existing and developing strategies for targeting altered splicing in cancer.
To explore therapeutic approaches for cancers dependent on spliceosome function.

Main Methods:

Targeting global splicing in cancers dependent on wild-type splicing.
Modulating post-translational modifications of splicing-regulating proteins.
Interfering with aberrant splicing events and protein-RNA interactions.

Main Results:

Several therapeutic strategies are in development to target cancer splicing.
These strategies aim to disrupt spliceosome dependency and correct aberrant splicing.

Conclusions:

Targeting the spliceosome and aberrant splicing presents a promising therapeutic avenue for cancer treatment.
Further research into these strategies could lead to novel cancer therapies.

Read full analysis

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