Journal: Nature Communications

Article Title: Intrinsic resistance to RAS inhibitors is driven by dysregulation of KRAS degradation

doi: 10.1038/s41467-025-67109-5

Figure Lengend Snippet: A , B Hemalun eosin and Immunostaining analysis of KRAS-G12D and HA (corresponding to KRAS-WT overexpression) of lung tumor sections from the Kras-G12D; GFP and Kras-G12D; WT-KRAS-OE mice 10 weeks post-Cre injection. Scale bar, 50 µm. C Tumor nodule growth was assessed by tumor volumetric analysis of micro-CT scans in the indicated mice. Data are shown as mean ± SEM; n = 5 mice per group with p -value calculated by two-sided mixed model analysis with no adjustments. D Survival analysis in the indicated mice; n = 5 mice per group with p -value calculated using the Log-rank (Mantel-Cox) test. E Heatmaps illustrating the proximity-based interaction signals of KRAS proteins determined by BioID analysis. The data were extracted from , . F Relative GPS-based stability of KRAS proteins in HEK293T cells expressing sh GFP or sh LZTR 1. Data are shown as mean ± SEM, n = 4 technical replicates per group. G Immunoblot analysis of the indicated proteins in A427 and H727 cells expressing sh GFP or sh LZTR1 . The samples derive from the same experiment. LZTR1, KRAS-G12V, and Vinculin were detected on the same gel; total KRAS was run on a separate gel processed in parallel. Data are shown as mean ± SEM, n = 4 technical replicates per group. H KRAS mutations and LZTR1 alterations in the TCGA LUAD dataset obtained from cBioPortal. Homdel, homozygous deletion; hetloss, shallow deletion. n = 507 patients with co-occurence q -value calculated. I Immunoblot analysis of the indicated proteins in lung tumor cells isolated from individual mice at 14 weeks post-Cre injection. The samples derive from the same experiment. LZTR1, KRAS-G12D, and Vinculin were detected on the same gel; total KRAS was run on a separate gel processed in parallel. Data are shown as mean ± SEM, n = 4 mice per group with p -values calculated by two-sided Mann‒Whitney test. J Expression of RAS proteins in lung cancer cells isolated from the indicated mice by TMT-labeled MS proteomics. Data are shown as mean ± SEM, n = 4 mice per group with p -values calculated by two-sided Mann‒Whitney test. K Tumor nodule growth was assessed by tumor volumetric analysis of micro-CT scans. Data are shown as mean ± SEM; n = 12 mice per group with p -value calculated by two-sided mixed model analysis with no adjustments. L H&E staining of the lung tissues from the indicated mice at 6 and 14 weeks post-Cre injection. Scale bar, 100 µm.

Article Snippet: pDONR223-KRAS4B G12V , Addgene plasmid #81665.

Techniques: Immunostaining, Over Expression, Injection, Micro-CT, Expressing, Western Blot, Isolation, Labeling, Staining