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CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (I)

ABSTRACT: CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (I)

PROVIDER: PRJNA492454 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7889390_1.fastq.gz	Fastqsanger.gz
	SRR7889390_2.fastq.gz	Fastqsanger.gz
	SRR7889391_1.fastq.gz	Fastqsanger.gz
	SRR7889391_2.fastq.gz	Fastqsanger.gz
	SRR7889392_1.fastq.gz	Fastqsanger.gz

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CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (II)

Project description:Inactivating mutations in SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, underlie small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). To reveal its druggable vulnerabilities, we perform kinase-focused RNAi screens and uncover that SMARCA4-deficient SCCOHT cells are highly sensitive to the inhibition of cyclin-dependent kinase 4/6 (CDK4/6). SMARCA4 loss causes profound downregulation of cyclin D1, which limits CDK4/6 kinase activity in SCCOHT cells and leads to in vitro and in vivo susceptibility to CDK4/6 inhibitors. SCCOHT patient tumors are deficient in cyclin D1 yet retain the retinoblastoma-proficient/p16INK4a-deficient profile associated with positive responses to CDK4/6 inhibitors. Thus, our findings indicate that CDK4/6 inhibitors, approved for a breast cancer subtype addicted to CDK4/6 activation, could be repurposed to treat SCCOHT. Moreover, our study suggests a novel paradigm whereby critically low oncogene levels, caused by loss of a driver tumor suppressor, may also be exploited therapeutically.

2019-02-04 | GSE120298 | GEO

CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (I)

2019-02-04 | GSE120297 | GEO

CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary.

Project description: Not available

| S-EPMC6361890 | biostudies-literature

CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (II)

Project description:CDK4/6 inhibitors target SMARCA4-determined cyclin D1 deficiency in hypercalcemic small cell carcinoma of the ovary (II)

| PRJNA492456 | ENA

Gene expression in small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) cell line COV434

2025-04-02 | GSE217699 | GEO

Gene Expression of Small Cell Carcinoma of the Ovary, hypercalcemic type.

Project description:Small cell carcinoma of the ovary-hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer afflicting young women at a median age of 24 years. SCCOHTs are characterized by loss of protein expression of SWI/SNF chromatin remodeling ATPases SMARCA4 and SMARCA2 through mutation and epigenetic silencing, respectively. This study aims to establish gene expression profiles of this cancer through RNA-Seq of four pathologically confirmed cases of SCCOHT tumors.

2018-02-20 | GSE109919 | GEO

Re-expression of SMARCA4/BRG1 in Small Cell Carcinoma of Ovary, Hypercalcemic Type (SCCOHT) promotes an epithelial-like gene signature through an AP-1-dependent mechanism

Project description:Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is a rare and aggressive form of ovarian cancer. SCCOHT tumors have inactivating mutations in SMARCA4 (BRG1), one of the two mutually exclusive ATPases of the SWI/SNF chromatin remodeling complex. To address the role that BRG1 loss plays in SCCOHT tumorigenesis, we performed integrative multi-omic analyses in SCCOHT cell lines +/- BRG1 re-expression. BRG1 re-expression induced a gene and protein signature similar to an epithelial cell and gained chromatin accessibility sites correlated with other epithelial originating TCGA tumors. Furthermore, AP-1 motifs were enriched at the promoters of highly upregulated epithelial genes. Using a dominant negative AP-1 cell line, we found that both AP-1 DNA binding activity and BRG1 re-expression are necessary for the gene and protein expression of epithelial genes. Our study demonstrates that BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon AP-1 activity.

2021-01-15 | PXD014134 | Pride

SMARCA4 loss is synthetic lethal with CDK4/6 via restriction CCND1 chromatin accessibility in lung cancer

Project description:Tumor suppressor SMARCA4 (BRG1), a key SWI/SNF chromatin remodelling gene, is frequently inactivated in cancers which is not directly druggable. We recently uncovered that SMARCA4 loss in an ovarian cancer subtype causes cyclin D1 deficiency leading to susceptibility to CDK4/6 inhibition. Here, we show that this vulnerability is conserved in non-small cell lung cancer (NSCLC), where SMARCA4 loss also results in reduced cyclin D1 expression and selective sensitivity to CDK4/6 inhibitors. In addition, SMARCA2, another SWI/SNF subunit lost in a subset of NSCLCs, also regulates cyclin D1 and drug response when SMARCA4 is absent. Mechanistically, SMARCA2/4 loss reduces cyclin D1 expression by a combination of restricting CCND1 chromatin accessibility and suppressing c-jun, a transcription activator of CCND1. Furthermore, SMARCA4 loss is synthetic lethal with CDK4/6 inhibition both in vitro and in vivo, suggesting that FDA-approved CDK4/6 inhibitors could be effective to treat this significant subgroup of NSCLCs.

2019-01-03 | GSE121755 | GEO

Combined CDK4/6 and PD-1 Inhibition in Refractory SMARCA4-Deficient Small-Cell Carcinoma of the Ovary, Hypercalcemic Type.

Project description: Not available

| S-EPMC7377332 | biostudies-literature

Germline and somatic SMARCA4 mutations characterize small-cell carcinoma of the ovary, hypercalcemic type.

Project description:Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is the most common undifferentiated ovarian malignancy in women under 40 years1. We sequenced the exomes of six individuals from three SCCOHT families. After discovering segregating deleterious germline mutations in SMARCA4 in all three families, we tested DNA from a fourth family, which also possessed a segregating SMARCA4 germline mutation. All familial tumors sequenced harboured either a somatic mutation or loss of the wild-type allele. Immunohistochemical (IHC) analysis of these and additional familial and non-familial cases showed loss of the SMARCA4 protein (BRG1) in 38/40 tumors overall. Sequencing of cases with available DNA revealed at least one germline or somatic deleterious SMARCA4 mutation in 30/32 cases. Additionally, the SCCOHT cell line BIN-67 contained bi-allelic deleterious mutations in SMARCA4. Our findings identify alterations in SMARCA4 as the major cause of SCCOHT, which could lead to genetic counseling and new treatment approaches.

| EGAS00001000721 | EGA

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