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Tumorigenicity of KRAS-ablated pancreatic cancer cells requires STAT3 function

GSE275858 Mus musculus Expression profiling by high throughput sequencing 4 samples Submitted 2025/02/05 Platform GPL30172
Summary
Oncogenic KRAS mutations underlie some of the deadliest human cancers. Genetic or pharmacological KRAS inactivation produces mixed outcomes, ranging from complete regression to frequent relapse. Mechanisms underpinning the resistance of cancer cells to KRAS inactivation remain to be understood. Here we investigate a conceptual framework of pancreatic ductal adenocarcinoma showing that CRISPR-mediated KRAS ablation impedes tumor growth contingent on the concomitant inactivation of the STAT3 transcription factor. Mechanistically, the incurred losses of KRAS and STAT3 disrupt a temporal balance between tumor cell differentiation, proliferation, and self-renewal. This in turn impairs tumor growth in mice and enhances their immune rejection, resulting in tumor clearance. Our findings identify a specific role for STAT3 in supporting cancer cell fitness with a particular focus on KRAS-inhibited tumors and provide a rationale for developing therapies targeting mutant KRAS and STAT3.
Published in
Intratumor heterogeneity in KRAS signaling shapes treatment resistance
Petrenko O, Kirillov V, D'Amico S et al. · iScience 2025 · PMID 39898020 · doi:10.1016/j.isci.2024.111662
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Also filed as BioProject PRJNA1153379 and SRA study SRP529106. Searching any of these in the dataset finder brings you back here.

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