Fig. 1. SOS1/2 genetic ablation protects from KRAS^G12D-driven LUAD in mice.

a Schematic illustration of the experimental strategy applied to all different genotypic groups. Animals of the indicated KRAS and SOS1/2 genotypes were equally treated with TMX after 1 month of age and then analyzed during the ensuing months at the timepoints indicated in the following panels. b Kaplan–Meier survival plots for SOS1/2^WT (black), SOS1^KO (red) and SOS2^KO (blue) animals analyzed in our model of RAS^G12D-driven LUAD. n = 20 (SOS1/2^WT), n = 25 (SOS1^KO), n = 28 (SOS2^KO); *P = 0.0107 vs SOS1/2^WT. Log-rank (Mantel-Cox) test. c Percentage of O₂ saturation in blood of 12-month-old SOS1/2^WT/KRAS^WT and KRAS^G12D mice of the SOS1/2 genotypes. n = 4 independent mice per genotype. **P = 0.0097 vs SOS1/2^WT/KRAS^G12D; ^##P = 0.0068 vs SOS2^KO. Data shown as mean ± SD. One-way ANOVA and Tukey’s test. d Total number of KRAS^G12D-mutant tumors present on the surface of the lungs of 1, 3, and 5 months-old SOS1/2^WT, SOS1^KO, or SOS2^KO mice. n = 6 independent mice per genotype. Data shown as mean ± SD. At 3 months: **P = 0.0067 vs SOS1^KO and **P = 0.0052 vs SOS2^KO; at 5 months: **P = 0.0018 vs SOS1^KO and *P = 0.0424 vs SOS2^KO). One-way ANOVA and Tukey’s test. e Representative lung microCT scan images for each age and genotype. f Progression of LUAD tumor volume in the groups and timepoints indicated. n = 3 independent mice per genotype. Data expressed as mean ± SD. At 1 month: ^#P = 0.0201 vs SOS1^KO and P = 0.0052 vs SOS2^KO; at 5 months: *P = 0.0382 vs SOS1^KO and ^#P = 0.0264 vs SOS2^KO). One-way ANOVA and Tukey’s test. g Percentage distribution of the histopathological grades exhibited by KRAS^G12D lung tumors of the indicated genotypes and timepoints. Hyperproliferating Type II Pneumocytes (HPNII, black bars), adenoma (orange bars) or advanced grade adenoma (light blue bars). h, i KRAS^G12D-driven tumor progression examined in lungs of 1 to 12-month-old KRAS^G12D-mutant mice of the indicated genotypes. h Representative H&E-stained sections of lungs from animals of the indicated age and genotype. Scale bars, 1 mm. i Kinetics of tumor burden progression from 1-month-old to 12-month-old mice of the indicated genotypes. n = 4 independent mice per genotype and timepoint. Data shown as mean ± SD. At 3 months: *P = 0.0176 vs SOS2^KO; ****P < 0.0001 vs SOS1^KO and ^##P = 0.0019 vs SOS2^KO; at 5 months: ***P ≤ 0.001 vs SOS1^KO and SOS2^KO and ^###P = 0.0008 vs SOS2^KO; at 7 months: ***P = 0.0002 vs SOS1^KO and *P = 0.0164 vs SOS2^KO and ^#P = 0.0195 vs SOS2^KO; at 9 months: ***P = 0.0002 vs SOS1^KO and *P = 0.0195 vs SOS2^KO and ^#P = 0.0243 vs SOS2^KO; at 12 months: **P = 0.0019 vs SOS1^KO. One-way ANOVA and Tukey’s test. Source data are provided as a Source data file.