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内容記述 |
Purpose: Pancreatic cancer is an intractable cancer with a 5-year survival rate still below 10%. In this study, we aim to clarify the biological effects and molecular mechanisms of a new cutting-edge heavy-ion radiotherapy system using ions heavier than carbon (C), such as O- and Ne-ions, which are likely to effectively kill intractable cancer, especially in combination with a KRAS inhibitor.Methods: Human pancreatic cancer cells PANC1 (KRAS G12D mutant) and MiaPaCa2 (KRAS G12C mutant) were treated with multi-ion beam IR alone or in combination with sotorasib (KRAS G12C inhibitor) and MRTX1133 (KRASG12D inhibitor), then the cell viability, RT-qPCR, western blotting and RNA-sequencing analyses were performed. Results: MiaPaCa2 (KRAS G12C mutant) cells were relatively sensitive to multi-ion beams (Ne, O, C, He), and this effect was further enhanced by combining with KRAS G12C-specific inhibitors sotorasib and adagrasib. In comparison, PANC1 (G12D mutant) cells were resistant to multi-ion beams (He-, C-, O-ions except Ne-ion), but were sensitized when combined with MRTX1133, a G12D-specific inhibitor, whereas no effect was observed when combined with sotorasib. Real-time qPCR analysis demonstrated that C-, Ne-, and O-ion beams aberrated the expression of apoptotic-and autophagy-related genes in different ways, independent of KRAS mutant status. The RNA-sequencing KEGG pathway analysis showed that heavier ion species, such as O- and Ne-ions, combined with KRAS inhibitor predominantly suppressed Wnt, PI3K/AKT, EGFR-signaling pathway and enhanced PD-L1 expression in KRAS mutant pancreatic cancer cells.Conclusions: Multi-ions such as O- and Ne-ion beam IR combined with KRAS inhibitors effectively killed KRAS mutant pancreatic cancer cells with apoptosis and autophagy induction and demonstrated a potential high response to immune checkpoint inhibitor (ICI) immunotherapy. |
