Figure 2 from Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC for Immune Checkpoint Blockade

Le résumé fourni par la source

RAS(ON) inhibitor doublet forestalls resistance driven by elevated RAS pathway flux. A, Antitumor activity of elironrasib and daraxonrasib as single agents or in combination in the NCI-H2122 (KRASG12C/G12CSTK11mutKEAP1mut, NSCLC) subcutaneous xenograft model (n = 8–15 per group). Tumor-bearing mice were treated with vehicle or RAS(ON) inhibitors (elironrasib at 100 mg/kg orally every day and daraxonrasib at 25 mg/kg orally every day as single agents or in combination) for 17 to 56 days. Mean tumor volumes of each group were plotted over the course of treatment. Vehicle control and specific treatment groups were compared by two-way repeated-measures ANOVA on the last measurement day of the vehicle group (***, P < 0.001; ****, P < 0.0001). The dotted line indicates the initial average tumor volume. Error bars, SEM. B, Antitumor activity of elironrasib and daraxonrasib as single agents or in combination in NCI-H2030 (KRASG12C/G12CSTK11mutKEAP1mut, NSCLC) subcutaneous xenograft model (n = 8 per group). Tumor-bearing mice were treated with vehicle or RAS(ON) inhibitors (elironrasib at 100 mg/kg orally every day and daraxonrasib at 25 mg/kg orally every day as single agents or in combination) for 21–89 days. Mean tumor volumes of each group were plotted over the course of treatment. Vehicle control and specific treatment groups were compared by two-way repeated-measures ANOVA on the last measurement day of the vehicle group (****, P < 0.0001). The dotted line indicates the initial average tumor volume. Error bars, SEM. C, Histopathology analysis of HER2 in eight KRASG12C-mutant NSCLC subcutaneous xenograft tumors at baseline included in the tumor response waterfall plot and Kaplan–Meier analysis in Fig. 1. Representative images are shown at 60× magnification. Scale bars, 50 μm. D, Antitumor activity of elironrasib, daraxonrasib, and elironrasib plus daraxonrasib combination in CTG-2536 (KRASG12C/WT, HER2High, NSCLC) subcutaneous PDX model (n = 4–6 per group). Tumor-bearing mice were treated with vehicle or RAS(ON) inhibitors (elironrasib at 200 mg/kg orally every day, daraxonrasib at 25 mg/kg orally every day, and combination of elironrasib at 200 mg/kg orally every day plus daraxonrasib at 25 mg/kg orally every day) for 16–90 days. Mean tumor volumes of each group were plotted over the course of treatment. Vehicle control and specific treatment groups were compared by two-way repeated-measures ANOVA on the last measurement day of the vehicle group, and none of the comparisons were statistically significant. The dotted line indicates the initial average tumor volume. Error bars, SEM. E, Antitumor activity of elironrasib, daraxonrasib, and elironrasib plus daraxonrasib combination in the LUN055 (KRASG12C Amp, NSCLC) subcutaneous PDX model (n = 3 per group). Tumor-bearing mice were treated with vehicle or RAS(ON) inhibitors (elironrasib at 100 mg/kg orally every day, daraxonrasib at 25 mg/kg orally every day and combination of elironrasib at 30 mg/kg orally every day plus daraxonrasib at 25 mg/kg orally every day) for 21–91 days. Mean tumor volumes of each group were plotted over the course of treatment. Vehicle control and specific treatment groups were compared by two-way repeated-measures ANOVA on the last measurement day of the vehicle group (*, P < 0.05). The dotted line indicates the initial average tumor volume. Error bars, SEM. Two tumor volume plots were from two different studies. F, Relative copy numbers of KRASWT or KRASG12C in LUN055 (KRASG12C Amp, NSCLC) subcutaneous PDX tumors (n = 2–3 per group) collected at the end of tumor growth studies as shown in E. Tumors used for ddPCR analysis were collected at 3 hours after the last dose of vehicle or inhibitors. The relative gene copy numbers were determined by ddPCR and normalized to RPP30. Specific treatment group was compared with vehicle control using one-way ANOVA followed by Dunnett multiple comparison test (*, P < 0.05; **, P < 0.01). G, DNA FISH, RNA ISH, and histopathology analysis of LUN055 (KRASG12C Amp, NSCLC) subcutaneous PDX tumors collected at the end of tumor growth studies as shown in E. Representative images are shown at 63×, 40×, and 40× magnification from ROIs closest to the mean of the group for FISH, RNA ISH, and IHC, respectively. Tumors used for representative images were collected at 3 hours after the last dose of vehicle or elironrasib. Scale bars, 50 μm. Cen12, centromere 12; ROI, region of interest; po, orally; qd, every day.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.