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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]

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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]

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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.

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

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Targeting cancer with small molecule pan-KRAS degraders

Project description:Despite the high prevalence of cancers driven by KRAS mutations, to date only the G12C mutation has been clinically proven to be druggable via covalent targeting of the mutated cysteine amino acid residue1. However, in many cancer indications other KRAS mutations, such as G12D and -V, are far more prevalent and small molecule concepts that can address a wider variety of oncogenic KRAS alleles are in high clinical demand2. Here we show that a single small molecule can be used to simultaneously and potently degrade 13 out of 17 of the most prevalent oncogenic KRAS alleles, including those not yet tractable by inhibitors. Compared with inhibition, degradation of oncogenic KRAS results in more profound and sustained pathway modulation across a broad range of KRAS mutant cell lines. As a result, KRAS degraders inhibit growth of the majority of cancer cell lines driven by KRAS mutations while sparing models without genetic KRAS aberrations. Finally, we demonstrate that pharmacological degradation of oncogenic KRAS leads to tumour regression in vivo. Together, these findings unveil a new path towards addressing KRAS driven cancers with small molecule degraders. This is the proteomics analysis of ACBI3 and compoun 8, its negative control.

2024-10-01 | PXD050650 | Pride

Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation

Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.

2016-04-19 | PXD003223 | Pride

ADAM9 deficiency mediates KRAS related pathways in pancreatic cancer cells

Project description:Kirsten rat sarcoma virus (KRAS) signaling drives pancreatic ductal adenocarcinoma (PDAC) malignancy, which is an unmet clinical need. Here we identify a disintegrin and metalloproteinase domain 9 (ADAM9) as a modulator of PDAC progression via stabilization of wild-type and mutant KRAS proteins. Mechanistically, ADAM9 loss increases the interaction of KRAS with plasminogen activator inhibitor-1 (PAI-1), which functions as a selective autophagy receptor in conjunction with LC3, triggering the lysosomal degradation of KRAS. Suppression of ADAM9 by a small molecule inhibitor restricts disease progression in spontaneous models, and the combination with gemcitabine elicits dramatic regression of patient-derived tumors. Our findings provide a promising strategy to target the KRAS signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in PDAC.

2023-12-11 | GSE245560 | GEO

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