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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE120298 | GEO | 2019/02/04

REPOSITORIES: GEO

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

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 | GSE120297 | GEO

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

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

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

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

| PRJNA492454 | ENA

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

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

siRNA profiling of human cell line IMR-32 at time point 0 and transiently transfected with siRNA against GFP, Cyclin D1 and CDK4 at time point 48 hours reveals the undifferentiated phenotype in neuroblastoma depends on Cyclin D1 and CDK4 activity

Project description:Genomic aberrations of Cyclin D1 (CCND1) and CDK4 in neuroblastoma indicate that dysregulation of the G1 entry checkpoint is an important cell cycle aberration in this pediatric tumor. Here we report that analysis of Affymetrix expression data of primary neuroblastic tumors shows an extensive over-expression of Cyclin D1 and CDK4 which correlates with histological subgroups and prognosis respectively. Immunohistochemical analysis demonstrated an over-expression of Cyclin D1 in neuroblasts and a low Cyclin D1 expression in all cell types in ganglioneuroma. This suggests an involvement of G1 regulating genes in neuronal differentiation processes which we further evaluated using RNA interference against Cyclin D1 and its kinase partner CDK4 in several neuroblastoma cell lines. This resulted in pRb pathway inhibition as shown by an almost complete disappearance of CDK4 specific pRb phosphorylation; reduction of E2F transcriptional activity and a decrease of Cyclin A protein levels. The Cyclin D1 and CDK4 knock-down resulted in a significant reduction in cell proliferation, a G1 specific cell cycle arrest and moreover an extensive neuronal differentiation. Affymetrix microarray profiling of siRNA treated cells revealed a shift in expression profile towards a neuronal phenotype. Several new potential downstream players are identified. We conclude that neuroblastoma functionally depend on over-expression of G1 regulating genes to maintain their undifferentiated phenotype. Experiment Overall Design: The Cell line IMR-32 at time point 0 and transiently transfected with siRNA against GFP, Cyclin D1 and CDK4 at time point 48 hours. All experiments are biological triplicates.

2008-10-25 | E-GEOD-8866 | biostudies-arrayexpress

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 [ChIP-seq]

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 a SCCOHT cell line +/- 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. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. 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 the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2020-12-30 | GSE151018 | 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 [CUT&RUN]

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 a SCCOHT cell line +/- 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. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. 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 the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2021-01-04 | GSE162626 | 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 [RNA-seq]

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 a SCCOHT cell line +/- 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. Gained chromatin accessibility and BRG1 recruited sites were strongly enriched for transcription factor binding motifs of AP-1 family members. 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 the BRG1 re-expression drives an epithelial-like gene and protein signature in SCCOHT cells that depends upon by AP-1 activity.

2020-12-30 | GSE151025 | GEO

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