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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

JUN is a master mediator of resistance to MAPK pathway inhibition in KRAS-mutant pancreatic ductal adenocarcinoma.

Project description:Pancreatic ductal adenocarcinoma (PDAC) is often driven by KRAS mutations, but inhibitors targeting the most frequent KRAS substitutions in PDAC are not yet approved in the clinic. We previously discovered that KRAS-mutant PDAC are sensitive to the combination of SHP2 and ERK inhibitors, recently investigated in the Phase I/Ib clinical trial NCT04916236. Lately, RAS(ON) multi-selective inhibitors have entered clinical development, representing a promise for mono or combination therapies in PDAC. However, resistance may arise even for combination therapies. Here, we aimed at anticipating mechanisms of resistance to SHP2 plus ERK or RAS(ON) multi-selective inhibitors. Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression. Functional genetic and pharmacological experiments pointed at JUN as the most downstream resistance mediator, and indirect therapeutic target, using MAP2K4 inhibitors. Alterations in the PI3K/AKT/mTOR and JUN pathways may serve as biomarkers for sensitivity/resistance in clinical trials testing MAPK inhibitors combinations in KRAS-mutant PDAC.

2026-03-04 | GSE303578 | GEO

Ubiquitin-driven signaling organization sustains MAPK output under KRAS inhibition in pancreatic ductal adenocarcinoma: Comparative LC-MS/MS analysis of MKRN1-dependent ubiquitination sites on its substrate YES1

Project description:This project contains the mass spectrometry data supporting the study of the E3 ubiquitin ligase MKRN1 in regulating therapeutic resistance to KRAS inhibition in pancreatic ductal adenocarcinoma (PDAC). The project includes three independent datasets: 1) AP-MS-based interactome profiling to identify MKRN1-interacting proteins in human PDAC AsPC-1 cells; 2) Comparative LC-MS/MS analysis to map MKRN1-dependent ubiquitination sites on its core substrate YES1; 3) Global quantitative phosphoproteomic profiling of the MKRN1-YES1 axis to identify downstream effectors sustaining MAPK pathway activation in PDAC. All data are associated with the manuscript entitled "Ubiquitin-driven signaling organization sustains MAPK output under KRAS inhibition in pancreatic ductal adenocarcinoma".

2026-03-19 | PXD075906 |

KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition.

Project description: Not available

| S-EPMC11733531 | biostudies-literature

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

JUN is a master mediator of resistance to MAPK pathway inhibition in KRAS-mutant pancreatic ductal adenocarcinoma.

Project description:JUN is a master mediator of resistance to MAPK pathway inhibition in KRAS-mutant pancreatic ductal adenocarcinoma.

| PRJNA1295861 | ENA

Prolonged KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals Therapeutic Opportunities.

Project description:Direct targeting of KRAS to inhibit the MAPK cascade is poised to transform the therapeutic landscape of pancreatic ductal adenocarcinoma (PDAC). However, analyses of PDAC samples from patients treated with KRASG12C inhibitors have revealed secondary mutations restoring MAPK signaling and promoting epithelial-to-mesenchymal transition (EMT) as key mechanisms of acquired resistance. Here, we show that human PDAC specimens and patient-derived cell lines treated with the ERK inhibitor ulixertinib display upregulation of EMT-associated and inflammatory gene programs, particularly those linked to the interferon response. Using the GeneRep-nSCORE computational framework to reconstruct and rank regulatory networks enriched in ERKi and KRASi-resistant PDAC cells, we identified TRIM22, an interferon-inducible E3 ubiquitin ligase, as a critical mediator of EMT and treatment resistance. Mechanistically, TRIM22 promotes proteasomal degradation of IκBα, leading to activation of NF-κB signaling, a known driver of EMT. Notably, we identify TACSTD2, encoding Trophoblast Cell Surface Antigen 2 (TROP2), as an NF-κB target gene upregulated following EMT. Functionally, combining ulixertinib or the KRAS inhibitor MRTX1133 with the TROP2-directed antibody-drug conjugate sacituzumab govitecan significantly suppressed the growth of PDAC patient-derived xenografts. Together, our work identifies TRIM22 as a molecular link between interferon signaling and EMT and reveals TROP2 as a druggable vulnerability to sustain the therapeutic efficacy of KRAS-MAPK pathway inhibitors.

2026-03-25 | GSE303051 | GEO

Prolonged KRAS-MAPK Inhibition Induces Interferon-mediated Epithelial-to-Mesenchymal Transition and Reveals Therapeutic Opportunities

2026-03-25 | GSE302981 | GEO

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

| PRJNA923658 | ENA

Phosphoinositide 3-kinase regulates basal wild-type RAS signaling to confer resistance to KRAS inhibition

Project description:Despite the availability of RAS inhibitors and the dependence of >90% of pancreatic ductal adenocarcinomas (PDAC) on oncogenic KRAS mutations, resistance to KRAS inhibition remains a serious obstacle. We show here that phosphoinositide 3-kinase (PI3K) plays a major role in this resistance through upstream activation of wild-type RAS signaling – beyond its known KRAS effector function. Combining proximity labeling, CRISPR screens, live-cell imaging, and functional assays we found that PI3K orchestrates phosphoinositide-mediated GAB1 recruitment to the plasma membrane, nucleating assembly of RAS signaling complexes that activate mitogen-activated protein kinase (MAPK) in an EGFR/SHP2/SOS1-dependent manner. We further demonstrate that inhibiting PI3K enhances sensitivity to mutant-specific KRAS inhibitors in PDAC cells, including cells with clinically identified PIK3CA mutations. Our findings refine RAS-PI3K signaling paradigms, reveal that PI3K-driven wild-type RAS activation drives resistance to KRAS inhibition, and illuminate new avenues for augmenting KRAS-targeted therapies in PDAC.

2026-04-27 | PXD065233 | Pride

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