SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer

Xue, Yibo; Meehan, Brian; Fu, Zheng Qing; Wang, Xue Qing D.; Fiset, Pierre; Rieker, Ralf J.; Levins, Cameron; Kong, Tim; Zhu, Xianbing; Morin, Geneviève; Skerritt, Lashanda; Herpel, Esther; Venneti, Sriram; Martı́nez, Daniel; Judkins, Alexander R.; Jung, Sungmi; Camilleri-Broët, Sophie; Gonzalez, Anne V.; Guiot, Marie‐Christine; Lockwood, William W.; Spicer, Jonathan; Agaimy, Abbas; Pastor, William A.; Dostie, Josée; Rak, Janusz; Foulkes, William D.; Huang, Sidong

doi:10.1038/s41467-019-08380-1

Cited by 144 publications

(135 citation statements)

References 54 publications

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“…Therefore, we do not expect that the 424 downregulation of cyd-1 alone is responsible for the tight cell-cycle arrest. Remarkably, two recent human cancer studies also concluded that SWI/SNF ATPases promote cyclin D1 426 20 expression (Xue et al 2019b(Xue et al , 2019a. This was found to underlie a synthetic lethal interaction between CDK4/6 inhibition and SMARCA4 loss in SCCOHT ovarian carcinoma and non-small 428 cell lung cancers.…”

Section: Acute Swi/snf Depletion Leads To Cell Division Arrest Beforementioning

confidence: 96%

Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferationin vivo

Vaart

Godfrey

Portegijs

et al. 2019

Preprint

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20SWI/SNF complexes regulate transcription through chromatin remodeling and opposing gene silencing by Polycomb-group (PcG) proteins. Genes that encode SWI/SNF subunits are 22 frequently mutated in human cancer. The selective advantage, subunit bias, and common heterozygosity of such mutations remains poorly understood. Here, we characterized how 24 functional loss of various SWI/SNF subunits and PcG EZH2 affect proliferation-differentiation decisions in vivo, making use of the reproducible development of the nematode C. elegans. We 26 applied a lineage-specific genetics strategy to create partial or complete SWI/SNF subunit loss, as well as double gene knockout with PcG EZH2. Our data show that a high SWI/SNF BAF 28 dosage is needed to oppose Polycomb-mediated transcriptional repression and to arrest cell division during differentiation. In contrast, even in the absence of the PcG EZH2-related 30 methyltransferase, a low level of the SWI/SNF BAF complex is necessary and sufficient to sustain cell proliferation and hyperplasia. Our data provide experimental support for the theory 32 that during carcinogenesis partial SWI/SNF BAF loss-of-function mutations are selected because they eliminate a tumor suppressor activity while maintaining an essential transcription regulatory 34 function. 36 suppressor (Rb) protein family of transcriptional co-repressors, CDK-inhibitory proteins (CKIs) 42 that bind and block cyclin-dependent kinases (CDKs), and the anaphase-promoting complex in association with the coactivator Cdh1/FZR1 (APC/C-FZR1), which promotes protein 44 degradation (Ruijtenberg and van den Heuvel 2016). In addition to these general regulators of the cell cycle, lineage-specific transcription factors and chromatin regulators coordinate the arrest of 46 cell division with terminal differentiation. In particular, SWI/SNF (switch/sucrose nonfermenting) chromatin remodeling complexes have been found to play an important role in this 48 process (Ruijtenberg and van den Heuvel 2015; Yu et al. 2013; Joliot et al. 2014; Albini et al. 2015). 50 SWI/SNF chromatin remodeling complexes are large, multi-subunit protein complexes, initially 52 identified as positive regulators of gene expression in yeast (for review, (Mathur and Roberts 2018)). The conserved components of SWI/SNF complexes were independently identified in 54 Drosophila melanogaster as antagonists of Polycomb-mediated transcriptional repression, and found in mammals through homology searches. Multiple distinct SWI/SNF subcomplexes are 56 modularly assembled from a variety of different subunits. These SWI/SNF complexes contain an ATPase core subunit and use the energy generated by ATP hydrolysis to alter nucleosome 58

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Section: Acute Swi/snf Depletion Leads To Cell Division Arrest Beforementioning

confidence: 96%

Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferationin vivo

Vaart

Godfrey

Portegijs

et al. 2019

Preprint

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“…The inhibitors of Cdk6 were shown to be a promising agents in the treatment of various tumors via suppressing G1/S phases progression of the cell cycle. Cdk inhibition also upregulated immediate senescence of small cell lung cancer cell, and Cdk4/6 inhibitors were found to be effective on treatment of NSCLC . Therefore, we evaluated the hypothesis that HNF1A‐AS1, together with the downstream regulators miR‐149‐5p/Cdk6, may be involved in the regulation of NSCLC progression.…”

Section: Introductionmentioning

confidence: 99%

“…Cdk inhibition also upregulated immediate senescence of small cell lung cancer cell, 23 and Cdk4/6 inhibitors were found to be effective on treatment of NSCLC. [24][25][26] Therefore, we evaluated the hypothesis that HNF1A-AS1, together with the downstream regulators miR-149-5p/Cdk6, may be involved in the regulation of NSCLC progression.…”

Section: Introductionmentioning

confidence: 99%

lncRNA HNF1A‐AS1 modulates non–small cell lung cancer progression by targeting miR‐149‐5p/Cdk6

Liu

Chen

et al. 2019

J of Cellular Biochemistry

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Growing evidence have shown the important regulation of lncRNAs (long noncoding RNAs) in non–small cell lung cancer (NSCLC). lncRNA hepatocyte nuclear factor 1 homeobox A (HNF1A)‐antisense RNA 1 (AS1), an “oncogene”, was reported to regulate human tumors progression. However, the molecular mechanism of HNF1A‐AS1 involved in the development of NSCLC is still under investigation. In the current study, we found that HNF1A‐AS1 was relatively upregulated in both NSCLC patient tissues and cell lines. Functional studies established that overexpression of HNF1A‐AS1 promoted cell proliferation, cell cycle, invasion, and migration of NSCLC cells in vitro. The promotion abilities of HNF1A‐AS1 on NSCLC cell progression were suppressed via knockdown of HNF1A‐AS1. miR‐149‐5p was then proved to be a novel target of HNF1A‐AS1, whose expression was negatively correlated with HNF1A‐AS1 in NSCLC patient tissues and cell lines. HNF1A‐AS1 increased the expression of cyclin‐dependent kinase 6 (Cdk6) via sponging with miR‐149‐5p. Gain‐ and loss‐of‐functional studies indicated that HNF1A‐AS1 promoted NSCLC progression partially through inhibition of miR‐363‐3p and induction of Cdk6. Subcutaneous xenotransplanted tumor model confirmed that interference of HNF1A‐AS1 suppressed the tumorigenic ability of NSCLC via upregulation of miR‐149‐5p and downregulation of Cdk6 in vivo. In conclusion, our findings clarified the biologic significance of the HNF1A‐AS1/miR‐149‐5p/Cdk6 axis in NSCLC progression and provided novel evidence that HNF1A‐AS1 may be a new potential therapeutic target for the treatment of NSCLC.

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“…Thus, TOP2 dysfunction in BAF complex‐deficient tumors, such as ARID1A‐deficient cancers, results in aberrant DNA replication and chromosomal segregation. Based on the abnormality of those cellular functions, BAF complex‐deficient cancer cells are selectively sensitive to inhibitors of the cell cycle regulators cyclin‐dependent kinase (CDK)4/CDK6, the DNA replication checkpoint factor ATR, and the chromosomal segregation factor Aurora kinase A …”

Section: Synthetic Lethal Targets Based On Targeting the Function Of mentioning

confidence: 99%

“…ARID1A mediates the physical interaction between the BAF complex and TOP2. 42 [43][44][45][46][47] The SWI/SNF chromatin remodeling complex is involved in the regulation of several metabolic pathways. The energy supply in cancer cells is derived from ATP generated by the glycolytic pathway.…”

Section: Synthe Ti C Le Thal Targ E Ts Ba S Ed On Targ E Ting the Fmentioning

confidence: 99%

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

Sasaki

Ogiwara

2020

Cancer Science

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The SWI/SNF chromatin remodeling complex is composed of approximately 15 subunits, and approximately 20% of all cancers carry mutations in the genes encoding these subunits. Most of the genetic alterations in these genes are loss‐of‐function mutations. The identification of vulnerability based on synthetic lethality in cancers with SWI/SNF chromatin remodeling complex deficiency contributes to precision medicine. The SWI/SNF chromatin remodeling complex is involved in transcription, DNA repair, DNA replication, and chromosomal segregation. Cancers with deficiency in the SWI/SNF chromatin remodeling complex show increased vulnerability derived from the loss of these functions. Synthetic lethal targets have been identified based on vulnerabilities in the functions of the SWI/SNF chromatin remodeling complex. In this review article, we propose a precision medicine strategy using chemotherapeutic methods, such as molecular targeted therapy and immunotherapy, based on harnessing synthetic lethality in cancers with deficiency in the SWI/SNF chromatin remodeling complex.

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SMARCA4 loss is synthetic lethal with CDK4/6 inhibition in non-small cell lung cancer

Cited by 144 publications

References 54 publications

Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferationin vivo

Dose-dependent functions of SWI/SNF BAF in permitting and inhibiting cell proliferationin vivo

lncRNA HNF1A‐AS1 modulates non–small cell lung cancer progression by targeting miR‐149‐5p/Cdk6

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

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