Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

PANCREATIC DUCTAL ADENOCARCINOMAS RESISTANT TO KRAS INHIBITION ARE DRUGGABLE WITH AN ANTI-MUC1-C ADC

ABSTRACT: Treatment of pancreatic ductal carcinomas (PDACs) has been advanced by the development of KRAS mutant inhibitors. Despite this progress, PDACs invariably develop resistance to these agents by mechanisms that largely remain unclear. The MUC1 gene, which encodes an oncogenic MUC1-C protein, is upregulated in PDAC KRAS G12D tumors. We report that treatment of PDAC cells with the selective KRAS G12D MRTX1133 inhibitor is associated with induction of MUC1-C expression. We show that KRAS G12D inhibition activates a MUC1-C/NF-B p65 auto-inductive pathway. Our results further demonstrate that MUC1-C drives resistance to MRTX1133 by activating the inflammatory IFN type I and II pathways. Of clinical relevance, targeting MUC1-C genetically and pharmacologically reverses MRTX1133 resistance and is synergistic in combination with MRTX1133 treatment. In leveraging MRTX1133-induced upregulation of MUC1-C expression, an anti-MUC1-C (M1C) antibody-drug conjugate (ADC) is highly effective against MRTX1133-resistant PDAC KRAS G12D cell lines, patient-derived organoids and PDX tumor xenograft models. These findings demonstrate that MUC1-C confers resistance of PDAC KRAS G12D mutant cells to MRTX1133 and identify MUC1-C as a target for M1C ADC treatment of PDAC patients who are refractory to MRTX1133 treatment.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293756 | GEO | 2025/04/08

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer

Project description:KRAS inhibitors demonstrate clinical efficacy in pancreatic ductal adenocarcinoma (PDAC); however, resistance is common. Among patients with KRASG12C-mutant PDAC treated with adagrasib or sotorasib, mutations in PIK3CA and KRAS, and amplifications of KRASG12C, MYC, MET, EGFR, and CDK6 emerged at acquired resistance. In PDAC cell lines and organoid models treated with the KRASG12D inhibitor MRTX1133, epithelial-to-mesenchymal transition and PI3K-AKT-mTOR signaling associate with resistance to therapy. MRTX1133 treatment of the KrasLSL-G12D/+;Trp53LSL-R172H/+;p48-Cre (KPC) mouse model yielded deep tumor regressions, but drug resistance ultimately emerged, accompanied by amplifications of Kras, Yap1, Myc, and Cdk6/Abcb1a/b, and co-evolution of drug-resistant transcriptional programs. Moreover, in KPC and PDX models, mesenchymal and basal-like cell states displayed increased response to KRAS inhibition compared to the classical state. Combination treatment with KRASG12D inhibition and chemotherapy significantly improved tumor control in PDAC mouse models. Collectively, these data elucidate co-evolving resistance mechanisms to KRAS inhibition and support multiple combination therapy strategies.

2024-06-17 | GSE269313 | GEO

Mechanisms of resistance to oncogenic KRAS inhibition in pancreatic cancer

2024-06-17 | GSE269985 | GEO

Treatment-Resistant Prostate Cancer Stem Cell Plasticity Governed by MUC1-C Uncovers a Common target for ADC Treatment

Project description:Androgen receptor positive prostate cancer (PC), castration resistant prostate cancer (CRPC) and neuroendocrine prostate cancer (NEPC) represent a spectrum of malignancies that invariably become resistant to treatment with targeted and cytotoxic agents. There is no known common pathway responsible for these pleotropic mechanisms of resistance. The MUC1 gene is aberrantly expressed in CRPC and NEPC in association with poor clinical outcomes. The present results demonstrate that the oncogenic MUC1-C protein is necessary for resistance of (i) PC cells to enzalutamide (ENZ), and (ii) CRPC and NEPC cells to docetaxel (DTX). We show that MUC1-C-mediated ENZ and DTX resistance is conferred by upregulation of aerobic glycolysis and suppression of reactive oxygen species (ROS) necessary for self-renewal capacity. Common dependence of these drug-resistant phenotypes on MUC1-C for the cancer stem cell (CSC) state thus identified a potential new target for their treatment. cIn this context, we further demonstrate that targeting MUC1-C with an antibody-drug conjugate (ADC) is highly effective in suppressing (i) self-renewal of drug-resistant CRPC and NEPC CSCs and (ii) growth of t-NEPC tumor xenografts derived from drug-resistant cells and a patient with refractory disease. These findings reveal a shared MUC1-C-dependent pathway in drug-resistant CRPC and NEPC progression and identify MUC1-C as a target for their treatment with an ADC.

2025-02-16 | GSE289308 | GEO

Dual inhibition of KRASG12D and pan-ERBB is synergistic in pancreatic ductal adenocarcinoma

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a low survival rate. Recently, new drugs that target KRASG12D, a common mutation in PDAC, have been developed. We studied one of these compounds, MRTX1133, and found it was specific and effective at low nanomolar concentrations in patient-derived organoid models and cell lines harboring KRASG12D mutations. Treatment with MRTX1133 upregulated the expression and phosphorylation of EGFR and HER2, indicating that inhibition of ERBB signaling may potentiate MRTX1133 anti-tumor activity. Indeed, the irreversible pan-ERBB inhibitor, afatinib, potently synergized with MRTX1133 in vitro, and cancer cells with acquired resistance to MRTX1133 in vitro remained sensitive to this combination therapy. Finally, the combination of MRTX1133 and afatinib led to tumor regression and longer survival in orthotopic PDAC mouse models. These results suggest that dual inhibition of ERBB and KRAS signaling may be synergistic and circumvent the rapid development of acquired resistance in patients with KRAS mutant pancreatic cancer.

2023-06-09 | GSE234449 | GEO

Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction

Project description:The KRAS G12D mutation is a key oncogenic driver in many solid tumors, including pancreatic, gastric, and colorectal cancers. While recent preclinical studies have characterized features associated with innate and acquired KRAS G12D inhibitor resistance, strategies to overcome resistance, especially in the gastrointestinal cancer context, remain underexplored. Here, we generated nine gastrointestinal cancer models of acquired resistance to the KRAS G12D-selective inhibitor MRTX1133. We identified the enrichment of angiogenesis, hypoxia, and epithelial-to-mesenchymal transition (EMT) in an isogenic patient-derived organoid model of acquired resistance by single-cell RNA sequencing. In the nine resistant models, VEGFA expression and VEGFR2 phosphorylation were unanimously increased. Subsequent mechanistic studies revealed that an autocrine VEGFA signaling loop, initiated by an increased interaction between KRAS and PI3Kγ, drives both EMT and RAS independence. Elevated mitochondrial oxidative stress in resistant cells led to CCT2-mediated KRAS stabilization, thereby enhancing PI3Kγ activity. Moreover, we observed that cancer-vascular paracrine signaling both amplified angiogenesis and EMT signatures in cancer cells and promoted endothelial cell proliferation. Significantly, disruption of VEGFA signaling reversed EMT induction and restored sensitivity to MRTX1133. Concordantly, in mouse xenograft models, the combination of anti-VEGFR2 therapy and MRTX1133 rechallenge significantly reduced tumor growth, angiogenesis, and proliferation markers without adverse effects on body weight. These findings identify a critical role for VEGFA signaling in resistance to KRAS G12D inhibition and provide a rationale for combination therapies targeting angiogenesis in gastrointestinal cancers.

2025-03-02 | GSE290487 | GEO

Angiogenesis blockade overcomes acquired KRAS G12D inhibitor resistance driven by KRAS-PI3Kγ interaction [scRNA-Seq]

2025-03-03 | GSE290526 | GEO

Global mRNA expression profiling of murine primary PDAC cells following JQ1 or SAHA monotherapy as well as JQ1-SAHA combination therapy

Project description:Global mRNA expression profiles of murine primary PDAC cells following JQ1 or SAHA monotherapy as well as JQ1-SAHA combination therapy were collected using Affymetix mouse whole genome array (Mouse Genome 430A 2.0 Array) . Primary PDAC cells isolated from Ptf1aCre/+;Kras+/LSL-G12D;p53lox/lox (Kras;p53) mice were treated either with JQ1 (100 nM) or SAHA (2000 nM) or vehicle 10% (2-Hydroxypropyl)-β-cyclodextrin (Sigma-Aldrich) or as combination therapy with the indicated dosage for monotherapy. Total RNA isolation was performed after 6 hours of treatment. Primary PDAC cells from Ptf1aCre/+;Kras+/LSL-G12D;p53lox/lox (Kras;p53) mice treated either with JQ1, SAHA, vehicle or JQ1-SAHA combination were analyzed by global gene expression analysis.

2015-09-20 | E-GEOD-64836 | biostudies-arrayexpress

RNA-SEQ analysis of pancreatic ductal adenocarcinoma tumours in Pdx1-Cre;lsl-KRas[G12D] (KC), Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC), Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM];c-Myc[fl/+] (KMC-Mycfl/+), and Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM];Zbtb17[fl/fl] mice (KMC-Miz1fl/fl)

Project description:Activation of endogenously expressed KRas[G12D] in the pancreas of mice gives rise primarily to early stage PanIN lesions, however such lesions can occasionally progress to end-stage ductal adenocarcinoma (PDAC). Progression of KRas[G12D]- initiated lesions to PDAC is accelerated by modest expression of MYC from the Rosa26 locus. Deletion of 1 copy of endogenous c-Myc or both copies of endogenous Zbtb17 (aka Miz1), slows progression to PDAC and extends healthful survival of Pdx1-Cre;lsl-KRas[G12D];Rosa26-lsl-MYC[DM] (KMC) mice. Tumours were removed from mice with all 4 genotypes and validated by histological examination prior to RNA-SEQ analysis.

2020-03-16 | E-MTAB-8797 | biostudies-arrayexpress

Gene expression analysis between the pancreatic tissues of Pdx1-cre;Kras LSL-G12D and Pdx-cre;KrasLSL-G12D;IKK2/beta F/F mice

Project description:Constitutive Kras and NF-kB activation is identified as signature alterations in human pancreatic ductal adenocarcinoma (PDAC). Here, we report that pancreas-targeted IKK2/beta inactivation inhibited NF-kB activation and completely suppressed PDAC development. Our findings demonstrated that NF-kB is required for development of pancreatic ductal adenocarcinoma that was initiated by Kras activation. Pancreatic tissue from 4 groups of mice were used in this project: (1) the pancreas normal appearance of Pdx1-cre;KrasLSL-G12D;IKK2/beta mice, (2) the normal pancreas of Pdx1-cre;KrasLSL-G12D mice, (3) the pancreatic lesion of pancreatic intraepithelial neoplasia (PanIN) of Pdx1-cre;KrasLSL-G12D mice, and (4) the pancreatic lesion of PDAC of Pdx1-cre;KrasLSL-G12D mice. Each group included three mice. RNA samples from mouse pancreas were hybridized on GeneChip Mouse Gene 1.0 ST arrays (Affymetrix). Group (1) and group (2) were compared, and group (2), group (3) and group (4) were compared.

2012-01-24 | E-GEOD-33322 | biostudies-arrayexpress

Identification of MUC1-C Dependence in Drug-Resistant Advanced Prostate Cancer Uncovers a New Target for Antibody-Drug Conjugate Therapy

2025-01-02 | GSE276890 | GEO