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Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway

ABSTRACT: Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway

PROVIDER: PRJNA503479 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8146180_1.fastq.gz	Fastqsanger.gz
	SRR8146180_2.fastq.gz	Fastqsanger.gz
	SRR8146181_1.fastq.gz	Fastqsanger.gz
	SRR8146181_2.fastq.gz	Fastqsanger.gz
	SRR8146178_1.fastq.gz	Fastqsanger.gz

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Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway

Project description:Loss of FAT1 promotes resistance to CDK4/6 inhibitors. This study was to compare the differential mRNA expression of FAT1 crispr cells with parental cells, to identify the underlying mechanisms of resistance.

2018-11-02 | GSE122088 | GEO

Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway.

Project description:Cyclin dependent kinase 4/6 (CDK4/6) inhibitors (CDK4/6i) are effective in breast cancer; however, drug resistance is frequently encountered and poorly understood. We conducted a genomic analysis of 348 estrogen receptor-positive (ER+) breast cancers treated with CDK4/6i and identified loss-of-function mutations affecting FAT1 and RB1 linked to drug resistance. FAT1 loss led to marked elevations in CDK6, the suppression of which restored sensitivity to CDK4/6i. The induction of CDK6 was mediated by the Hippo pathway with accumulation of YAP and TAZ transcription factors on the CDK6 promoter. Genomic alterations in other Hippo pathway components were also found to promote CDK4/6i resistance. These findings uncover a tumor suppressor function of Hippo signaling in ER+ breast cancer and establish FAT1 loss as a mechanism of resistance to CDK4/6i.

| S-EPMC6294301 | biostudies-literature

Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway

Project description:To determine whether genomic alterations in pre-treatment tumor samples might be associated with resistance to CDK4/6 inhibitors (CDK4/6i) in patients with metastatic breast cancer, we subjected 348 ER+/HER2- breast cancer tumor samples to targeted sequencing using MSK-IMPACT assay. A total of 15 tumors did not harbor somatic non-synonymous mutations and were not included in this submission. All the tumors were procured prior to initiation of any of the three clinically efficacious CDK4/6i (palbociclib, ribociclib or abemaciclib; although the majority of patients received palbociclib in this cohort). We then performed an analysis to determine the association between somatic mutations and copy number alterations inferred to be biologically and therapeutically relevant with progression-free survival on CDK4/6i.

2018-11-08 | PRJEB29597 | EVA

HDAC inhibitors induce transcriptional activation of Hippo pathway signaling and is associated with improved outcomes in Hormone Receptor positive breast cancer

Project description:Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Treatment modalities for HR (+) metastatic breast cancer (mBC) includes endocrine therapy (tamoxifen, fulvestrant, aromatase inhibitors) in addition to targeted therapies (CDK4/6 inhibitors, PI3K/AKT/mTOR inhibitors, histone deacetylase (HDAC) inhibitors, and others. The hippo pathway LATS1/2-YAP/TAZ-TEAD signaling cascade is a fundamentally important pathway that governs multiple essential biological functions in cell biology and cancer biology. YAP/TAZ are often viewed as pro-tumorogenic, however, recent studies support a role of YAP as a tumor suppressor in HR (+) breast cancer due to its inhibition of estrogen signaling. Few studies have investigated the link between HDAC inhibitors and the Hippo pathway. In our study, we demonstrate that HDAC inhibitors induce transcriptional downregulation of YAP expression, while conversely activating a TEAD mediated transcriptional program with upregulation of many Hippo pathway canonical genes. We further identified 4 genes (CCDC80, GADD45A, F3, TGFB2) that were upregulated by HDAC inhibitors and associated with significantly improved survival in a HR (+) breast cancer cohort. We also correlate in patients samples from a clinical cohort of HR (+) metastatic breast cancer that upregulation of Hippo downstream genes are correlated with improved outcomes. Our study provide a novel mechanistic explanation for the clinical benefit of HDAC inhibitors, while providing further experimental support that Hippo-TEAD transcriptional activation profile is associated with better outcomes in HR (+) breast cancer.

2025-03-05 | GSE263971 | GEO

TNBC response to CDK4/6 inhibitors plus RANKL inhibitors

Project description:TNBC response to CDK4/6 inhibitors plus RANKL inhibitors

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Project description:Loss of the FAT1 tumor suppressor promotes resistance to CDK4/6 inhibitors via the Hippo pathway

| PRJEB29597 | ENA

FAT1 knockdown in immortalized astrocyte and glioma cell lines

Project description:The FAT1 gene was knocked down using 2 independent siRNAs, in immortalized human astrocytes and U87 and U251 glioma cell lines. A non-targeted scramble siRNA was used as a control. Scramble, FAT1 siRNA#1 and FAT1 siRNA#2 were transfected into each cell line, in duplicate, and RNA analyzed using the Affymetrix U133A 2.0 platform.

2013-01-10 | E-GEOD-40583 | biostudies-arrayexpress

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

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

2019-02-04 | GSE120298 | GEO

CDK4/6 inhibitors plus RANKL inhibitors in syngeneic TNBC model

Project description:CDK4/6 inhibitors plus RANKL inhibitors in syngeneic TNBC model

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