Chromatin remodellers as therapeutic targets

Area of Science:

• Cancer Genomics
• Epigenetics
• Molecular Biology

Background:

• Chromatin regulators, particularly SWI/SNF (Switch/Sucrose Non-Fermentable) complexes, are frequently mutated in various cancers.
• Mutations in SWI/SNF subunits are implicated in oncogenesis and linked to neurodevelopmental disorders.
• Other chromatin remodellers (ISWI, CHD, INO80/SWR) also play roles in cancer and development.

Purpose of the Study:

• To review the structure, function, and disease relevance of SWI/SNF and related chromatin remodelling complexes.
• To elucidate mechanisms by which SWI/SNF mutations contribute to cancer and neurological diseases.
• To explore therapeutic strategies targeting these complexes and synthetic lethal vulnerabilities.

Main Methods:

• Analysis of large-scale cancer genome sequencing data.
• Review of studies on oncogene cooperation with SWI/SNF.
• Examination of genome-wide perturbation screens in cancer cell lines.
• Summary of clinical trial data for SWI/SNF-targeting drugs.

Main Results:

• Over 20% of cancers harbor mutations in SWI/SNF complex genes.
• SWI/SNF dysfunction contributes to cancer transformation and neurodevelopmental disorders.
• Synthetic lethal targets and therapeutic compounds, including an FDA-approved drug, have been identified.

Conclusions:

• Understanding SWI/SNF complex biology is crucial for cancer and developmental disorder research.
• Targeting SWI/SNF complexes and synthetic lethal interactions presents a viable therapeutic avenue.
• Ongoing research continues to uncover vulnerabilities and develop novel treatments.