Fig. 6: LKB1 loss in associated with MCL-dependence of KRASG12C-mutant NSCLC PDX tumors and patient tumor explants.
From: LKB1 regulates JNK-dependent stress signaling and apoptotic dependency of KRAS-mutant lung cancers
A KRASG12C-mutant NSCLC tumor cells were collected for BH3 profiling and assessment of BIM:MCL-1 interactions after ex vivo treatment with sotorasib or trametinib. B Change in MCL-1 (MS1 10 + 30 µM peptide) and BCL-XL (HRK 10 + 100 µM peptide) dependent priming of patient tumor cells after ex vivo treatment with 0.1 µM trametinib or 1 µM sotorasib treatment. Data is normalized to Vehicle control and error bar presents S.E.M. (N = 3,6. *p = 0.0476, unpaired-nonparametric t test, 2-sided). C Co-IP assessment of BIM:MCL-1 interaction in tumor cells isolated from pleural fluid after ex vivo treatment with 0.1 µM trametinib (T) or 1 µM sotorasib (S) for 16 h. Data is representatives of 2 independent biological replicates. D Mice bearing KRASG12C-mutant NSCLC patient derived xenograft (PDX) tumors were treated with sotorasib (100 mg/kg) for 3 days and harvested for BH3 profiling. Data shown is the difference in MCL-1 dependent priming (MS1 peptide) of sotorasib treated tumors normalized to vehicle control, each dot represents an independent mouse tumor with error bar as S.E.M. (N = 3–7, ***p = 0.0002, 2-way ANOVA). E Mice bearing KRASG12C-mutant NSCLC PDX tumors (LKB1-loss: MGH1112-1, MGH1138-1, MGH1196-2; LKB1 WT: MGH1062-1, MGH1145-1, MGH10199-3) were treated with vehicle, sotorasib (100 mg/kg), AMG 176 (50 mg/kg) or sotorasib (100 mg/kg) + AMG 176 (50 mg/kg) daily. Data shown are mean and S.E.M. of N = 6–10 animals per arm, statistical difference between single agent and combination arms was determined using mixed-effects model, ****p = 0.00001, *p = 0.013, 2-way ANOVA). F Survival curves of PDX tumor-bearing mice: the progression free survival (PFS) metric was determined by time to 20% increase in tumor volume from baseline measurement (****p = 0.0001, **p = 0.0087, Log-rank Mantel-Cox test). Source data are provided as a Source Data file. A–D Created in BioRender. Li, C. (2025) https://BioRender.com/p50l332.
