Transcriptomic profiling of KRAS mutants in a panel of isogenic human pancreatic ductal adenocarcinoma (PDAC) cell lines

Although distinct biochemical properties have been reported for individual KRAS mutants, a comprehensive characterization of allele-specific differences in PDAC cells remains unresolved. Here, we systematically interrogated the molecular consequences of seven common KRAS mutant variants by reconstituting 4 isogenic, KRAS-deficient PDAC cell lines and performing bulk RNA-sequencing.

We found that baseline cellular state, rather than allele identity, was the predominant driver of molecular variation across all samples. Pathway analyses highlighted that KRAS mutants upregulated inflammatory and immune-related pathways, including TNFα signaling via NFκB, IL2-STAT5 signaling, and epithelial–mesenchymal transition, while downregulating interferon responses and hypoxia-associated. Importantly, no robust allele-specific molecular programs were identified across all samples.