Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Sasaki, Minako; Ogiwara, Hideaki

doi:10.1111/cas.14311

Cited by 37 publications

(38 citation statements)

References 62 publications

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“…These genes include ARID2, PBRM1, and BRD7, three of the 29 genes that are known to code for the 15 subunits of the SWI/SNF complex. Genes of the SWI/SNF chromatin remodeling complex are mutated in over 20% of cancers, and several studies further suggest that tumors with deficiencies in these genes may show better responses to immunotherapy [72]. Loss of PBRM1 expression was shown to correlate with better response to immunotherapy in patients with clear cell renal carcinoma [73].…”

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confidence: 99%

BAP1: Not just a BRCA1-associated protein

Louie

Kurzrock

2020

Cancer Treatment Reviews

121

101

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BRCA1-Associated Protein 1 (BAP1) is a ubiquitin carboxy-terminal hydrolase that has been established as a tumor suppressor, utilizing its deubiquitinating activity to regulate a number of processes including DNA damage repair, cell cycle control, chromatin modification, programmed cell death, and the immune response. Mutations in the BAP1 gene commonly result in a number of aggressive cancers; predominantly uveal melanoma, malignant mesothelioma, renal cell carcinoma, and cutaneous melanoma. Importantly, germline mutations in the BAP1 gene have been established as a novel tumor predisposition syndrome, conferring an increased risk of hereditary, early-onset cancers. Current treatment options for cancers with BAP1 alterations are limited to standard therapies. However, several therapeutic avenues have been proposed to specifically target BAP1 alterations in cancer. Molecularly targeted approaches include histone deacetylase inhibitors and EZH2 inhibitors to target the role of BAP1 in chromatin modification and transcriptional regulation, respectively. PARP inhibitors and platinum chemotherapy agents have the potential to target BAP1-altered tumors, due to the role of BAP1 in DNA damage repair. Lastly, emerging reports suggest that BAP1-alterations in cancer confer distinct immunogenic phenotypes that may be particularly susceptible to novel cancer immunotherapies. This review aims to present a concise and up to date report on the BAP1 gene in cancer, surveying its functional roles, characteristics and clinical manifestations. Furthermore, we highlight the established and emerging therapeutic options for BAP1-mutated cancers.

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confidence: 99%

BAP1: Not just a BRCA1-associated protein

Louie

Kurzrock

2020

Cancer Treatment Reviews

121

101

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“…The EZH2 sensitivity to inhibitor therapy was shown to be dependent on the presence of mutations in secondary genes. In particular, the SWI/SNF subunit SMARCB1 has been approved as an effective marker of metastatic or locally advanced epithelioid sarcoma sensitivity to tazemetostat [26][27][28], while SMARCA2, SMARCA4, ARID1A, and PBRM1 are potential marker candidates [91][92][93][94]105]. The analysis of correlation between impairment of individual genes and the sensitivity of 777 cell lines to knockout of EZH2, SUZ12, or EED genes allowed us to predict new gene mutations as tentative markers for PRC2 inhibitor therapy.…”

Section: Discussionmentioning

confidence: 99%

Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types

Erokhin

Четверина

Győrffy

et al. 2021

Cancers

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PRC2 (Polycomb repressive complex 2) is an evolutionarily conserved protein complex required to maintain transcriptional repression. The core PRC2 complex includes EZH2, SUZ12, and EED proteins and methylates histone H3K27. PRC2 is known to contribute to carcinogenesis and several small molecule inhibitors targeting PRC2 have been developed. The present study aimed to identify the cancer types in which PRC2 targeting drugs could be beneficial. We queried genomic and transcriptomic (cBioPortal, KMplot) database portals of clinical tumor samples to evaluate clinical correlations of PRC2 subunit genes. EZH2, SUZ12, and EED gene amplification was most frequently found in prostate cancer, whereas lymphoid malignancies (DLBCL) frequently showed EZH2 mutations. In both cases, PRC2 alterations were associated with poor prognosis. Moreover, higher expression of PRC2 subunits was correlated with poor survival in renal and liver cancers as well as gliomas. Finally, we generated a Python application to analyze the correlation of EZH2/SUZ12/EED gene knockouts by CRISPR with the alterations detected in the cancer cell lines using DepMap data. As a result, we were able to identify mutations that correlated significantly with tumor cell sensitivity to PRC2 knockout, including SWI/SNF, COMPASS/COMPASS-like subunits and BCL2, warranting the investigation of these genes as potential markers of sensitivity to PRC2-targeting drugs.

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“…Due to the high degree of similarity in structure between BRG and BRM, mutation or epigenetic silencing of either ATPase can be compensated by expression of the other. Previous investigation has determined BRM to be an effective synthetic lethal target in BRG1-deficient cancer, and vice-versa (100, 101). The wide spectrum of phenotypic severity seen in both intellectual disorders and cancers that result from mutated or altered expression of the SWI/SNF ATPases is dependent on the dose of functional SWI/SNF in affected tissues (31, 33).…”

Section: Discussionmentioning

confidence: 99%

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasionin vivo

Smith

Xiao

et al. 2021

Preprint

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Chromatin remodeling complexes, such as the SWItching defective/Sucrose Non-Fermenting (SWI/SNF) ATP-dependent chromatin remodeling complex, coordinate metazoan development through broad regulation of chromatin accessibility and transcription, ensuring normal cell cycle control and cellular differentiation in a lineage-specific and temporally restricted manner. Mutations in subunits of chromatin regulating factors are associated with a variety of diseases and cancer metastasis co-opts cellular invasion found in healthy cells during development. Here we utilize Caenorhabditis elegans anchor cell (AC) invasion as an in vivo model to identify the suite of chromatin and chromatin regulating factors (CRFs) that promote cellular invasiveness. We demonstrate that the SWI/SNF ATP-dependent chromatin remodeling complex is a critical regulator of AC invasion, with pleiotropic effects on both G0/G1 cell cycle arrest and activation of invasive machinery. Using targeted protein degradation and RNA interference (RNAi), we show that SWI/SNF contributes to AC invasion in a dose-dependent fashion, with lower levels of activity in the AC corresponding to aberrant cell cycle entry and increased loss of invasion. Finally, we implicate the SWI/SNF BAF assembly in the regulation of the cell cycle, whereas our data suggests that the SWI/SNF PBAF assembly promotes AC attachment to the basement membrane (BM) and promotes the activation of the invasive machinery. Together these findings demonstrate that the SWI/SNF complex is necessary for two essential components of AC invasion: arresting cell cycle progression and remodeling the BM. The work here provides valuable single-cell mechanistic insight into the contributions of SWI/SNF assembly and subunit-specific disruptions to tumorigenesis and cancer metastasis.

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Synthetic lethal therapy based on targeting the vulnerability of SWI/SNF chromatin remodeling complex‐deficient cancers

Cited by 37 publications

References 62 publications

BAP1: Not just a BRCA1-associated protein

BAP1: Not just a BRCA1-associated protein

Clinical Correlations of Polycomb Repressive Complex 2 in Different Tumor Types

The SWI/SNF chromatin remodeling assemblies BAF and PBAF differentially regulate cell cycle exit and cellular invasionin vivo

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