Transcriptional and Epigenetic Plasticity Drive an Alternative Non-clonal Mechanism of Resistance to Kras G12D Inhibition in Pancreatic Cancer - PubMed
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- #Epigenetic Reprogramming
- #Pancreatic Cancer
- #KRAS Inhibitor Resistance
- In vivo experiments show mice inoculated with FC1242 cells develop resistance to KRASG12D inhibitor MRTX1133 after high-dose treatment.
- RNA sequencing reveals distinct gene expression changes in first- (M1R) and second-generation (M2R) resistant cell lines compared to nonresistant controls.
- Single-cell RNA sequencing analysis identifies distinct cellular clusters in sensitive and resistant cell lines, with resistant clusters overexpressing KRAS.
- Mesenchymal markers are overexpressed in MRTX1133-resistant cell lines, indicating an epithelial-mesenchymal transition (EMT) shift.
- DNA methylation sequencing shows progressive global demethylation in resistant cell lines, suggesting epigenetic reprogramming.
- Immunohistochemistry confirms a mesenchymal phenotypic shift in MRTX1133-resistant tumors, with increased markers like vimentin and α-SMA.