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Kras loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity

ABSTRACT: Kras loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity

PROVIDER: PRJNA1162093 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR30709300_1.fastq.gz	Fastqsanger.gz
	SRR30709300_2.fastq.gz	Fastqsanger.gz
	SRR30709301_1.fastq.gz	Fastqsanger.gz
	SRR30709301_2.fastq.gz	Fastqsanger.gz
	SRR30709302_1.fastq.gz	Fastqsanger.gz

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Kras loss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity

Project description:Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.

2024-09-22 | GSE277392 | GEO

Expression data from WT mice and bitransgenic Pdx1-cre/Kras*A mice bearing Pancreatic Ductal Adenocarcinoma

Project description:We have carried out transcriptional profile analysis in WT MICE and bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma Mouse models faithfully simulating human cancer are valuable for genetic identification of potential drug-targets but, among them, the most advantageous for practical use in subsequent preclinical testing of candidate therapeutic regimes are those exhibiting rapid tumor development. Considering that a KRAS mutation (predominantly in codon 12, such as KRASG12D; KRAS*) occurs with high frequency (~90%) in cases of human pancreatic ductal adenocarcinoma (PDA)1, we sought to develop a mouse PDA model that would exhibit high tumor incidence and short latency by ectopic overexpression of Kras*. Five WT mice and 6 bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma were used to identify key genes in the formation of panceatic malignacies

2014-09-01 | E-GEOD-53659 | biostudies-arrayexpress

Drug-class specific gene-based MAPK sensitivity scores predict sensitivity to MAPK inhibitors in pediatric low-grade gliomas

Project description:Drug-class specific gene-based MAPK sensitivity scores predict sensitivity to MAPK inhibitors in pediatric low-grade gliomas

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Drug-class specific gene-based MAPK sensitivity scores predict sensitivity to MAPK inhibitors in pediatric low-grade gliomas

Project description:Pediatric low-grade gliomas (pLGG) have shown heterogeneous responses to MAPK inhibitors (MAPKi) in clinical trials. A predictive feature for stratification is needed to identify patients likely to benefit from MAPKi therapy. MAPK-related genes differentially regulated between MAPKi sensitive and non-sensitive cell lines from the Genomics of Drug Sensitivity in Cancer dataset identified class-specific MAPKi sensitivity gene signatures used to calculate the MAPKi sensitivity score (MSS) via single sample gene set enrichment analysis. The MSS discerned gliomas with varying MAPK alterations from those without, and was higher in pLGG compared to other pediatric CNS tumors. As in clinical trials, the MSS was heterogeneous within pLGGs with a common MAPK alteration. A positive correlation between the MSS and the predicted immune infiltration determined by the ESTIMATE signature was observed. The MSS therefore represents a potential tool for the stratification of pLGG patients, worth of further investigation in upcoming clinical trials. Our data could support a role of microglia in the response to MAPKi, warranting further validation.

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Expression data from WT mice and bitransgenic Pdx1-cre/Kras*A mice bearing Pancreatic Ductal Adenocarcinoma

2014-09-01 | GSE53659 | GEO

Project description:MAPK inhibitor sensitivity scores (MSS) were developed to predict sensitivity to MAPK inhibitors in pediatric low-grade gliomas (pLGG). The scores were validated in pLGG cell lines in vitro and in the publicly available Open Pediatric Brain Tumor Atlas dataset. Validation in independent datasets is warranted.

2023-06-28 | GSE222405 | GEO

2023-06-28 | GSE222404 | GEO

Survival of pancreatic cancer cells lacking KRAS function

Project description:Activating mutations in the proto-oncogene KRAS are a hallmark of pancreatic ductal adenocarcinoma (PDAC), an aggressive malignancy with few effective therapeutic options. Despite efforts to develop KRAS-targeted drugs, the absolute dependence of PDAC cells on KRAS remains incompletely understood. Here we modeled complete KRAS inhibition using CRISPR/Cas-mediated genome editing. While KRAS knockout led to decreased in vitro proliferation and impaired in vivo tumorigenic growth, KRAS was dispensable in a subset of human and mouse PDAC cells. KRAS knockout cells exhibited hyperactivation of the PI3K pathway and induced sensitivity to phosphoinositide 3-kinase (PI3K) inhibitors. Mechanistically, PI3K inhibition in KRAS knockout cells led to transient mitogen-activated protein kinase (MAPK) blockade while impeding AKT-dependent 4EBP1 phosphorylation and cap-dependent translation. Furthermore, comparison of gene expression profiles of cells retaining or lacking KRAS revealed a novel functional role of KRAS in the suppression of metastasis-related genes. Accordingly, KRAS knockout gene expression signatures correlated with PDAC circulating tumor cell (CTC) signatures, and human PDAC tumors with gene expression patterns enriched in signatures from KRAS knockout cells were associated with worse survival in patients. Together, these data underscore the potential for resistance of PDAC to even the very best of KRAS inhibitors and suggest combination therapies with PI3K inhibitors as a viable strategy to circumvent resistance.

2017-10-23 | GSE71876 | GEO

Project description:MAPK-related gene signature predicting MAPKi sensitivity in pLGG

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Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma

Project description:Oncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup of mPDAC with therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype mPDAC, information regarding other types of mutations remain limited, and gene expression patterns associated with KRAS wildtype mPDAC have not been reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization of the molecular landscape of KRAS wildtype mPDAC and reveal increased frequency of chr1q amplification encompassing transcription factors PROX1 and NR5A2. By leveraging data from colorectal adenocarcinoma and cholangiocarcinoma samples, we highlight novel similarities between cholangiocarcinoma and KRAS wildtype mPDAC involving both mutation and expression-based signatures and validate these findings using an independent dataset. These data further establish KRAS wildtype mPDAC as a unique molecular entity, with therapeutic opportunities extending beyond gene fusion events.

2022-10-15 | PXD036632 | Pride

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