Simultaneous Targeting of KRAS and CDK4 Synergistically Induces Durable Growth Arrest in Pancreatic Cancer Cells [AsPC-1_RNA_Seq]
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE301148 | GEO | 2025/11/12
REPOSITORIES: GEO
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Project description:We report that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells (51T-2D cells) harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Mechanistically, the combinations induced sustained cell cycle arrest.
2025-11-12 | GSE301146 | GEO
Project description: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.
2025-04-08 | GSE293756 | GEO
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
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.
2025-03-03 | GSE290526 | GEO
Project description:The mechanism of action of a pan-Kras inhibitor MCB-294 remains unknown. We determined gene expression profiling in H358 and AsPC-1 cell line xenograft mouse models after MCB-294 treatment using RNA-seq analysis.
2024-02-22 | GSE249914 | GEO
Project description:The design of potent RAS inhibitors benefits from a molecular understanding of the dynamics in KRAS and NRAS and their oncogenic mutants. Here we characterize switch-1 dynamics in GTP-state KRAS and NRAS by 31P NMR, by 15N relaxation dispersion NMR, hydrogen-deuterium exchange mass spectrometry (HDX-MS), and molecular dynamics simulations. In GMPPNP-bound KRAS and NRAS, we see the co-existence of two conformational states, corresponding to an “inactive” state-1 and an “active” state-2, as previously reported. The KRAS oncogenic mutations G12D, G12C and G12V only slightly affect this equilibrium towards the “inactive” state-1, with rank order wt < G12C < G12D < G12V. In contrast, the NRAS Q61R oncogenic mutation shifts the equilibrium fully towards the “active” state-2. Our molecular dynamics simulations explain this by the observation of a transient hydrogen bond between the Arg61 side chain and the Thr35 backbone carbonyl oxygen. NMR relaxation dispersion experiments with GTP-bound KRAS Q61R confirm a drastic decrease in the population of state-1, but still detect a small residual population (1.8%) of this conformer. HDX-MS indicates that higher populations of state-1 correspond to increased hydrogen-deuterium exchange rates in some regions and increased flexibility, whereas low state-1 populations are associated with KRAS rigidification. We elucidated the mechanism of action of a potent KRAS G12D inhibitor, MRTX1133. Binding of this inhibitor to the switch-2 pocket causes a complete shift of KRAS G12D towards the “inactive” conformation and prevents binding of effector RAS-binding domain (RBD), by signaling through an allosteric network.
2025-05-07 | PXD054924 | Pride
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 | GSE269985 | GEO
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
Project description:Simultaneous Targeting of KRAS and CDK4 Synergistically Induces Durable Growth Arrest in Pancreatic Cancer Cells [AsPC-1_RNA_Seq]
| PRJNA1284191 | ENA
Project description:This is a Phase 1/2, open-label, multicenter, study evaluating the safety, tolerability, PK, PD, and anti-tumor activity of MRTX1133 in patients with advanced solid tumor malignancy harboring a KRAS G12D mutation.
| 9080 | ecrin-mdr-crc