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Mammalian SWI/SNF complexes in cancer: emerging therapeutic opportunities
Roodolph St Pierre1, Cigall Kadoch2
1Department of Pediatric Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA 02215; Broad Institute of MIT and Harvard, Cambridge, MA, USA; Chemical Biology Program, Harvard University, USA.
Abstract:
Mammalian SWI/SNF (BAF) chromatin remodeling complexes orchestrate a diverse set of chromatin alterations which impact transcriptional output. Recent whole-exome sequencing efforts have revealed that the genes encoding subunits of mSWI/SNF complexes are mutated in over 20% of cancers, spanning a wide range of tissue types. The majority of mutations result in loss of subunit protein expression, implicating mSWI/SNF subunits as tumor suppressors. mSWI/SNF-deficient cancers remain a therapeutic challenge, owing to a lack of potent and selective agents which target complexes or unique pathway dependencies generated by mSWI/SNF subunit perturbations. Here, we review the current landscape of mechanistic insights and emerging therapeutic opportunities for human malignancies driven by mSWI/SNF complex perturbation.
Insights
Mammalian SWI/SNF (BAF) complexes regulate gene expression. Mutations in these chromatin remodelers are common in cancer, suggesting they act as tumor suppressors, presenting therapeutic challenges.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Biology
Background:
- Mammalian SWI/SNF (also known as BAF) chromatin remodeling complexes are crucial for regulating gene transcription.
- Mutations in genes encoding SWI/SNF subunits are found in over 20% of human cancers.
- These mutations often lead to loss of protein expression, indicating SWI/SNF subunits function as tumor suppressors.
Purpose of the Study:
- To review current mechanistic insights into SWI/SNF-deficient cancers.
- To explore emerging therapeutic strategies for these malignancies.
Main Methods:
- Review of recent whole-exome sequencing data.
- Analysis of existing literature on SWI/SNF complex function and cancer genetics.
- Synthesis of information on therapeutic targets and dependencies in SWI/SNF-mutant cancers.
Main Results:
- SWI/SNF complexes play a significant role in maintaining genomic integrity and regulating transcription.
- Loss of SWI/SNF function contributes to tumorigenesis across diverse cancer types.
- Targeting specific vulnerabilities in SWI/SNF-deficient cancers is an active area of research.
Conclusions:
- SWI/SNF subunit mutations are a prevalent feature of human cancers, highlighting their tumor suppressor roles.
- Developing effective therapies for SWI/SNF-deficient cancers requires a deeper understanding of their unique biology.
- Further research into mechanistic insights and pathway dependencies is critical for advancing treatment options.