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TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [Methylation array]

ABSTRACT: TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [Methylation array]

PROVIDER: PRJNA1134247 | ENA |

REPOSITORIES: ENA

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TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [Methylation array]

Project description:Pancreatic ductal adenocarcinoma (PDAC) has one of the lowest cancer survival rates. Although KRAS oncogenes are responsible for the initiation of most PDACs, thus far KRAS inhibitors have not changed their clinical outcome. Here, we describe a therapeutic strategy that combines inhibition of three independent signaling nodes involved in downstream (RAF1), upstream (EGFR) and orthogonal (STAT3) KRAS signaling pathways. Genetic elimination and/or pharmacological inhibition/degradation of these independent nodes in orthotopic mouse tumor models results in their complete and durable regression. The efficacy of this therapeutic strategy has also been validated in several patient-derived organoid (PDO) and xenograft (PDX) PDAC tumor models using a combination of a Pan-ERBB inhibitor (Afatinib), a selective STAT3 PROTAC (SD36) and a RAF1 shRNA. Importantly, this triple strategy did not induce significant toxicities. These results open the door to the development of novel targeted therapies for PDAC patients.

2024-10-15 | GSE271987 | GEO

TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [RNA-seq]

2024-10-15 | GSE271518 | GEO

TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [RNA-seq]

Project description:TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION [RNA-seq]

| PRJNA1132151 | ENA

Rapid Target Engagement of KRAS G12C Tricomplex Inhibitor RO3903 Overcomes Resistance and Drives Durable Tumor Regression

Project description:Cysteine chemoproteomics data for paper "Rapid Target Engagement of KRAS G12C Tricomplex Inhibitor RO3903 Overcomes Resistance and Drives Durable Tumor Regression"

2025-12-04 | MSV000100113 | MassIVE

Synergy of chemotherapy and macrophage depletion leads to T cell memory activation and durable triple negative breast cancer regression

Project description:Chemotherapy and macrophage depletion leads to T cell memory activation and durable triple negative breast cancer regression in p53 null mouse models.

2022-06-10 | GSE173260 | GEO

Simultaneous Targeting of KRAS and CDK4 Synergistically Induces Durable Growth Arrest in Pancreatic Cancer Cells [AsPC-1_RNA_Seq]

Project description:We show that the KRAS-G12D inhibitor MRTX1133 synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells (AsPC-1) harboring KRAS-G12D 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 | GSE301148 | GEO

Simultaneous Targeting of KRAS and CDK4 Synergistically Induces Durable Growth Arrest in Pancreatic Cancer Cells [51T-2D_RNA_Seq]

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:TARGETING KRAS SIGNALING AT THREE INDEPENDENT NODES LEADS TO COMPLETE AND DURABLE PANCREATIC CANCER REGRESSION

| PRJNA1130922 | ENA

Simultaneous Targeting of KRAS and CDK4 Synergistically Induces Durable Growth Arrest in Pancreatic Cancer Cells

Project description:Mutant Ras oncoproteins, particularly KRAS, are among the most prevalent drivers of cancer. Small-molecule KRAS inhibitors have emerged as promising cancer therapeutics, yet resistance development remains a major hurdle. To overcome this challenge, we explored rational combination strategies aimed at enhancing therapeutic efficacy and durability. We show that the KRAS-G12C inhibitor Sotorasib synergizes with the CDK4/6 inhibitor Palbociclib to eliminate pancreatic ductal adenocarcinoma (PDAC) cells and organoids harboring KRAS-G12C mutations. This synergy was especially pronounced following drug washout, indicating a durable cellular response. Similar synergistic effects were observed in non-small-cell lung cancer (NSCLC) cells. Additionally, the KRAS-G12D inhibitor MRTX1133 cooperated with Palbociclib to suppress KRAS-G12D-mutant PDAC cells. Mechanistically, the combinations induced sustained cell cycle arrest, marked by reduced RB phosphorylation, decreased E2F1 expression, and increased levels of CDKN1B/p27. Deletion of CDKN1B largely reversed the growth-inhibitory effect, highlighting its essential role in mediating the observed synergy. In an orthotopic, immunocompetent mouse model of PDAC, MRTX1133 significantly delayed tumor growth and extended survival; however, despite its ability to suppress RB phosphorylation, Palbociclib failed to enhance these effects. This might be due to increased tumor vascularization upon Palbociclib treatment, as revealed by single cell RNA sequencing. In summary, our findings demonstrate the therapeutic potential of enhancing cell cycle restriction point activation in KRAS inhibitor-based therapies, while emphasizing the importance of precisely adjusting the drug combinations to the in vivo situation.

2025-12-18 | GSE311611 | GEO

Synergy of chemotherapy and macrophage depletion leads to T cell memory activation and durable triple negative breast cancer regression

Project description:Synergy of chemotherapy and macrophage depletion leads to T cell memory activation and durable triple negative breast cancer regression

| PRJNA698901 | ENA

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