Fig. 1: Polyamines synergistically enhance the efficacy of KRAS inhibitors in a KEAP1-dependent manner.
A Flow chart of the metabolic library screening process. Created in BioRender. Bian, Y. (2025) https://BioRender.com/3p0ref1. B Relative viability of metabolic-treated vs vehicle (DMSO)-treated MIAPACA2 cells showed the metabolic library screening results. MIAPACA2 cells were treated with KRAS G12C inhibitors sotorasib or adagrasib (MIAPACA2, sotorasib, IC50 = 40 nM; adagrasib, IC50 = 60 nM), along with metabolics contained in the library (MCE HY-L030) or vehicle (DMSO) for 72 h. The algorithm for “Relative viability” showed that “X” means a specific metabolic, “V” means vehicle (DMSO). C Relative viabilities of MIAPACA2 and H23 cells treated with gradient concentrations of spermine and KRASG12C inhibitors (sotorasib or adagrasib) for 72 h were shown. 2D surface response for cell viability and 3D surface Bliss synergy score were shown. (n = 3 independent experiments). D Relative viability of 15 pan-cancer KRASG12C mutant cell lines treated with vehicle (DMSO), spermine (100 nM), sotorasib (IC50), and combination (spermine and sotorasib) for 72 h. The cell lines including pancreatic adenocarcinoma cell line MIAPACA2; bladder urothelial carcinoma cell line UMUC3; esophageal squamous cell carcinoma cell line KYSE410; lung adenocarcinoma cell lines H23, H2122, LU99, SW1573, H2030, H1792, H358, LU65 and HCC44; ovarian epithelial tumor cell line OV56; and colorectal adenocarcinoma cell lines JVE-015 and SW1463. (n = 3 independent experiments) Data were analyzed by two-tailed Student’s t-test and were presented by mean ± SD. E Venn plot displayed two genes (KRAS and KEAP1) from the intersection of mutant genes in non-synergy effect cell lines, including H23, H2122, H2030, H1792, and HCC44. F Workflow of KRASG12C mutant PAAD and LUAD patient-derived organoids (PDOs) establishment. G The number of PAAD and LUAD organoids, accompanied by an informational schematic that includes the patients’ type of mutation and differentiation stage were shown. H, I Representative brightfield images of PAAD PDOs (from PAAD patient #1 and #4) (H) and LUAD PDOs (from LUAD patient #1 and #2) (I) treated with KRASG12C inhibitors (sotorasib, 300 nm; adagrasib, 300 nM), spermine (1000 nM) or combination for 72 h (scale bars, 100 μm). J–K Luminescence measurement showed the relative viability of PAAD PDOs (from PAAD patient #1 and #4) (J) and LUAD PDOs (from LUAD patient #1 and #2) (K) treated with KRASG12C inhibitors (sotorasib, 300 nm; adagrasib, 300 nM), spermine (1000 nM) or combination for 72 h. (n = 3 independent experiments) Data were analyzed by two-tailed Student’s t-test and were presented by mean ± SD. Source data are provided as a Source Data file.
