Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Cell cycle plasticity driven by MTOR signaling: integral mechanism for resistance to CDK4/6 inhibition

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC), like many KRAS-driven tumors, preferentially loses CDKN2A to bypass the RB tumor suppressive pathway. This finding and a gene expression profile indicative of a CDK4/6-driven cell cycle suggests that PDAC could be particularly sensitive to CDK4/6 inhibition. Analysis of a panel of patient-derived cell lines and xenografts indicates that many pancreatic cancers have an intrinsic resistance to CDK4/6 inhibition that is not due to known molecular mechanisms. Rather, there is a rapid and potent adaptive response that led to the upregulation of Cyclin D1 and Cyclin E proteins and compromised the suppression of a DNA replication gene expression program. These adaptive responses are dependent on MTOR signaling both in cell and animal studies. Strikingly, combination treatments with MTOR and CDK4/6 inhibitor had potent activity across a large number of patient derived models of PDAC underscoring the potential clinical efficacy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE113922 | GEO | 2019/05/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

De novo MYC addiction as an adaptive response of cancer cells to CDK4/6 inhibition

Project description:Cyclin-dependent kinases (CDK) are rational cancer therapeutic targets fraught with the development of acquired resistance by tumor cells. Through integrated fluxomics and transcriptomics approaches, we show that the inhibition of CDK4/6 causes enhanced metabolism of glucose, glutamine and amino acids, a metabolic reprogramming directed by the MYC transcription factor. Upon inhibition of CDK4/6, MYC is stabilized and its accumulation induces an upregulation of the mTOR pathway and increased glutamine metabolism and production of α-ketoglutarate, a prolyl hydroxylase substrate that triggers HIF1α hydroxylation and degradation. These MYC-driven adaptations to CDK4/6 inhibition render cells highly sensitive to inhibitors of mTOR and glutaminase and to hypoxia, revealing that drug resistance can mechanistically promote the emergence of new vulnerabilities that can be exploited therapeutically. We used microarrays to detail the global programme of gene expression underlying inhibition of CDK4 and CDK6.

2017-09-15 | GSE84597 | GEO

Cell cycle plasticity driven by MTOR signaling: integral mechanism for resistance to CDK4/6 inhibition

Project description:Cell cycle plasticity driven by MTOR signaling: integral mechanism for resistance to CDK4/6 inhibition

| PRJNA454470 | ENA

Endocrine-exocrine signaling in obesity-driven pancreatic ductal adenocarcinoma

Project description:Obesity is a major modifiable risk factor for pancreatic ductal adenocarcinoma (PDAC), yet how and when obesity contributes to PDAC progression is not well understood. Leveraging an autochthonous mouse model, we demonstrate a causal and reversible role for obesity in early PDAC progression, showing that obesity markedly enhances tumorigenesis, while genetic or dietary induction of weight loss intercepts cancer development. Bulk and single cell molecular analyses of human and murine samples define microenvironmental consequences of obesity that promote tumor development rather than new driver gene mutations. We observe increased inflammation and fibrosis and also provide evidence for significant pancreatic islet cell adaptation in obesity-associated tumors. Specifically, we identify aberrant beta islet cell expression of the peptide hormone cholecystokinin (CCK) in tumors as an adaptive response to obesity. Furthermore, islet CCK expression promotes oncogenic Kras-driven pancreatic ductal tumorigenesis. Our studies argue that PDAC progression is driven by local obesity-associated changes in the tumor microenvironment – rather than systemic effects – and implicate endocrine-exocrine signaling beyond insulin in PDAC development. Furthermore, our demonstration that these obesity-associated adaptations are reversible supports the use of anti-obesity strategies to intercept PDAC early during progression.

2020-08-12 | GSE137236 | GEO

Endocrine-exocrine signaling in obesity-driven pancreatic ductal adenocarcinoma

2020-05-14 | GSE131714 | GEO

Nucleolin aptamer N6L reprograms the translational machinery and acts synergistically with mTORi to inhibit pancreatic cancer proliferation

Project description:We previously showed that N6L, a pseudo-peptide that targets nucleolin, impairs pancreatic ductal adenocarcinoma (PDAC) growth and normalizes tumor vessels in animal models. In this study, we analyzed the translatome of PDAC cells treated with N6L to identify the pathways that were either repressed or activated. We observed a strong decrease of global protein synthesis. However, about 6% of the mRNAs were enriched in the polysomes. We identified a 5’TOP motif in many of these mRNAs, and demonstrated that a chimeric RNA bearing a 5‘TOP motif was up-regulated by N6L. We demonstrated that N6L activates the mTOR pathway which is required for the translation of these mRNAs. An inhibitory synergistic effect in PDAC cell lines including patient derived-xenografts and tumor derived-organoids was observed when N6L was combined with mTOR inhibitors. In conclusion, N6L reduces pancreatic cells proliferation which then undergoes a translational reprogramming through activation of the mTOR pathway. N6L and mTOR inhibitors act synergistically to inhibit the proliferation of PDAC and human PDX cell lines. This combotherapy of N6L and mTOR inhibitors could constitute a promising alternative to treat pancreatic cancer.

2021-10-20 | GSE184857 | GEO

Non-phosphorylatable cyclin D1 mutant potentiates endometrial hyperplasia and drives carcinoma with Pten loss

Project description:Cyclin D1 is a regulatory subunit of cyclin-Dependent Kinases 4 and 6 (CDK4/6) and regulates progression from G1 to S phase of the cell cycle. Dysregulated cyclin D1-CDK4/6 contributes to tumor development. Enforced expression of non-phosphorylatable cyclin D1T286A mutant, frequently observed in human cancers, drives tumorigenesis. However, physiological functions of cyclin D1T286A is unclear. We have generated a conditional knock-in mouse model where cyclin D1T286A is expressed under the control of its endogenous promoter, permitting us to study the precise functions of cyclin D1T286A in tumorigenesis. The expression of cyclin D1T286A from its endogenous promoter induces inflammation-mediated lymphocyte disorder and mesenteric tumor formation. Uterine-specific expression of cyclin D1T286A accelerates Pten loss driven endometrial hyperplasia to promote uterine cancer.

2023-04-04 | GSE188299 | GEO

Translational control of mTOR/4E-BP1 axis in MiaPaca-2 cells

Project description:Pancreatic ductal adenocarcinoma (PDAC) relies on hyper-activated protein synthesis. Consistently, human and mouse PDAC lose expression of the translational repressor and mTOR target 4E-BP1. Using genome-wide polysome-profiling, we here explore mRNAs whose translational efficiencies depend on the mTOR/4E-BP1 axis in Miapaca-2 cells. This was performed by isolating cytoplasmic and efficiently translated (heavy polysome-associated) mRNAs from MiaPaca-2 cells upon PP242-mediated mTOR inhibition

2019-09-18 | GSE137553 | GEO

Hierarchical clustering of PDAC cell lines

Project description:Hierarchical clustering of pancreatic cancer cell lines based on differentially regulated genes between mesenchymal and epithelial PDAC cells derived from primary tumours and metastases from KrasG12D-driven mouse models of pancreatic cancer.

2022-11-19 | E-MTAB-8173 | biostudies-arrayexpress

HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway via stimulating MSK1 kinase and suppressing PPP2R2B protein

Project description:Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, which lacks effective therapies. Here, we demonstrate that the transcription factor, HOXC6, is overexpressed in most PDACs, and its inhibition blocks PDAC tumor growth and metastasis. HOXC6 transcriptionally activates tumor-promoting kinase MSK1 and suppresses tumor-inhibitory protein PPP2R2B in PDAC. HOXC6-induced PPP2R2B suppression causes mTOR pathway activation, which facilitates PDAC growth. Also, MSK1 upregulation by HOXC6 is necessary for PDAC growth due to its ability to suppress apoptosis via its substrate DDX17. Combinatorial pharmacological inhibition of MSK1 and mTOR potently suppressed PDAC tumor growth and metastasis in PDAC mouse models. PDAC cells with acquired resistance to MSK1/mTOR-inhibitors displayed activated IGF1R signaling and were successfully eradicated by IGF1R inhibitor. Furthermore, MEK inhibitor trametinib enhanced the efficacy of dual MSK1 and mTOR inhibition. Collectively, these results identify therapeutic vulnerabilities of PDAC and an approach to overcome acquired drug resistance to prolong therapeutic benefit.

2023-10-30 | GSE150223 | GEO

HOXC6 drives a therapeutically targetable pancreatic cancer growth and metastasis pathway via stimulating MSK1 kinase and suppressing PPP2R2B protein

2023-10-30 | GSE150222 | GEO