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Adaptive resistance to SHP2-based vertical RAS-pathway inhibition in pancreatic cancer involves multifaceted routes towards dedifferentiation
2025-09-12
oncology
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BackgroundPancreatic ductal adenocarcinoma (PDAC) critically depends on oncogenic KRAS signaling. The Src-homology 2 domain-containing phosphatase 2 (SHP2) is essential for full KRAS activity. Allosteric SHP2 inhibition in vertical combination with mitogen-activated protein kinase (MAPK) or RAS inhibition demonstrates synergistic efficacy, delays the onset of resistance, and is currently being evaluated in clinical trials. MethodsEmploying a comprehensive set of models, including endogenous mur...
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