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In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts

ABSTRACT: In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts

PROVIDER: PRJNA893580 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22021923_1.fastq.gz	Fastqsanger.gz
	SRR22021923_2.fastq.gz	Fastqsanger.gz
	SRR22021924_1.fastq.gz	Fastqsanger.gz
	SRR22021924_2.fastq.gz	Fastqsanger.gz
	SRR22021925_1.fastq.gz	Fastqsanger.gz

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In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts [RNA-seq]

Project description:We evaluated the tumor efficacy of the CDK4/6 inhibitor palbociclib in two chordoma Patient’s Derived Xenograft (PDX) models to validate and identify novel therapeutic approaches.

2022-10-29 | GSE216418 | GEO

In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts [RNA-seq]

Project description:In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts [RNA-seq]

| PRJNA893589 | ENA

In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts [Target-seq]

Project description:In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts [Target-seq]

| PRJNA893590 | ENA

Investigating the target and off-target landscape of PLK1 small molecule inhibitor volasertib

Project description:In this study we aimed to identify off-targets of polo-like kinase 1 (Plk1) small molecule inhibitor volasertib. Plk1 is an important cell cycle kinase and an attractive target for anticancer treatment. Volasertib is ATP-competitive small molecules that may also block the ATP-pocket of other proteins. Despite the fatal infections and negative survival in a phase III trial on volasertib in acute myeloid leukemia volasertib has been a promising treatment option in children with rhabdomyosarcoma. Therefore, there is a need to understand the nature of adverse effects that possibly originate from the off-target proteins. We used thermal proteome profiling (TPP) to identify proteins that have a change in the thermal stability after treatment with volasertib. The temperature of aggregation of several proteins involved in prostaglandin and phosphatidyl-inositol phosphate metabolism increased after treatment with volasertib. PIP4K2A and ZADH2 were stabilized both by treatment in living cells and cell lysate. Functional disruption of these proteins affects the immune response and fatty acid metabolism. In addition, volasertib was found to affect transcriptional coactivators, normal and alternative RNA splicing regulators and proteins involved in the intracellular transport regulation. Our data suggests that the identified proteins may contribute more to the understanding of anti-tumor effect of volasertib.

2021-08-23 | PXD024040 | Pride

Investigating the target and off-target landscape of PLK1 small molecule inhibitor volasertib

2021-08-23 | PXD023757 | Pride

Gene expression alterations associated with acquired-resistance to the CDK4/6 inhibitor palbociclib [Palbociclib resistance_RNASeq]

Project description:RNA-seq was performed to compare the transcriptional programmes of palbociclib-resistant A375 and CHL1 cells compared to their parental counterparts Cyclin dependent kinase 4/6 (CDK4/6) inhibitors are an established treatment in estrogen receptor positive breast cancer and are currently in clinical development in melanoma; a tumour that exhibits high rates of CDK4 activation. We analyzed melanoma cells with acquired resistance to the CDK4/6 inhibitor palbociclib, and demonstrated that palbociclib-mediated inhibition of PRMT5 is essential for sensitivity to CDK4/6 inhibitors. Mechanistically, by inhibiting PRMT5 activity, palbociclib alters MDM4 pre-mRNA splicing leading to decreased MDM4 protein expression and subsequent p53 activation. In turn, p53 increases p21 leading to inhibition of CDK2, the main kinase substituting for CDK4/6 and a key driver of resistance to palbociclib. Loss of the ability of palbociclib to regulate the PRMT5-MDM4 axis leads to resistance. Importantly, combining palbociclib with the PRMT5 inhibitor GSK3326595 enhances the efficacy of palbociclib in treatment naïve and resistant models and also delays the emergence of resistance. Our studies have uncovered a novel mechanism of action of CDK4/6 inhibitors in regulating the MDM4 oncogene and the tumor suppressor, p53. Furthermore, we have established that palbociclib inhibition of the PRMT5-MDM4 axis is essential for robust melanoma cell sensitivity and provide pre-clinical evidence that co-inhibition of CDK4/6 and PRMT5 is an effective and well tolerated therapeutic strategy. Overall our data provides a strong rationale for further investigation of novel combinations of CDK4/6 and PRMT5 inhibitors in not only melanoma but other tumour types including breast, pancreatic and esophageal carcinoma.

2019-08-23 | GSE133567 | GEO

<i>In vivo</i> efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in human chordoma xenografts.

Project description:BackgroundManagement of advanced chordomas remains delicate considering their insensitivity to chemotherapy. Homozygous deletion of the regulatory gene CDKN2A has been described as the most frequent genetic alteration in chordomas and may be considered as a potential theranostic marker. Here, we evaluated the tumor efficacy of the CDK4/6 inhibitor palbociclib, as well as the PLK1 inhibitor volasertib, in three chordoma patient-derived xenograft (PDX) models to validate and identify novel therapeutic approaches.MethodsFrom our chordoma xenograft panel, we selected three models, two of them harboring a homozygous deletion of CDKN2A/2B genes, and the last one a PBRM1 pathogenic variant (as control). For each model, we tested the palbociclib and volasertib drugs with pharmacodynamic studies together with RT-PCR and RNAseq analyses.ResultsFor palbociclib, we observed a significant tumor response for one of two models harboring the deletion of CDKN2A/2B (p = 0.02), and no significant tumor response in the PBRM1-mutated PDX; for volasertib, we did not observe any response in the three tested models. RT-PCR and RNAseq analyses showed a correlation between cell cycle markers and responses to palbociclib; finally, RNAseq analyses showed a natural enrichment of the oxidative phosphorylation genes (OxPhos) in the palbociclib-resistant PDX (p = 0.02).ConclusionCDK4/6 inhibition appears as a promising strategy to manage advanced chordomas harboring a loss of CDKN2A/2B. However, further preclinical studies are strongly requested to confirm it and to understand acquired or de novo resistance to palbociclib, in the peculiar view of a targeting of the oxidative phosphorylation genes.

| S-EPMC9732546 | biostudies-literature

PLK1 inhibition selectively induces apoptosis in ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Project description:We have identified a synthetically lethal relationship between the loss of chromatin modulator, ARID1A, and the inhibition of PLK1 kinase through a mechanism that involves mitochondrial dysfunction. Using normal gastric epithelium cell line, GES1, we performed a comparative gene expression analysis comparing the various permutations of wild type (WT) and ARID1A knockout (KO) genotypes and untreated cells or those treated with PLK1 inhibitor,Volasertib. Consistent with ARID1A's role as a chromatin modulator, there was widespread gene expression modulation observed when comparing the WT cells with the ARID1A KO cells. In particular, we noted that oxidative phosphorylation and ROS pathway genes were enriched in ARID1A KO cells compared to wild type cells. Volasertib treatment appeared to exacerbate the effects on gene expression induced by ARID1A KO. We also investigated how ARID1A KO and Volasertib treatment specifically modulated the expression of mitochondrial encoded genes using a more recent human genome build, hg38 (as opposed to hg19), that enabled the correct alignment of these mitochondrial genes. For this analysis, in addition to GES1s, we used the ovarian cancer cell line, OVCAR3. To answer the question of which genes facilitate preferential cell killing of Volasertib-treated ARID1A KO cells, using normal breast epithelial cells, MCF10A, we performed a genome-wide CRISPR screen using the Brunello library. We identified many genes whose knockout made ARID1A KO cells resistant to Volasertib, many of which were involved in mitochondrial process.

2022-07-06 | GSE193942 | GEO

Gene expression alterations associated with acquired-resistance to the CDK4/6 inhibitor palbociclib [Palbociclib resistance_RNASeq]

Project description:Gene expression alterations associated with acquired-resistance to the CDK4/6 inhibitor palbociclib [Palbociclib resistance_RNASeq]

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In Vivo efficacy assessment of the CDK4/6 inhibitor palbociclib and the PLK1 inhibitor volasertib in Human Chordoma Xenografts

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-10-29 | GSE216419 | GEO