Figure 3 from Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC for Immune Checkpoint Blockade

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RAS(ON) inhibitor doublet drives sustained RAS signaling suppression, inhibits cell proliferation, and induces apoptosis in vivo. A, Target engagement of KRASG12C protein by elironrasib in NCI-H2122 (KRASG12C/G12CSTK11mutKEAP1mut, NSCLC) subcutaneous xenograft tumors, shown as the percentage of cross-linked KRASG12C by elironrasib relative to controls. Tumor-bearing mice were treated with 17 consecutive daily doses of elironrasib at 100 mg/kg as single agent (blue line) or in combination with daraxonrasib at 25 mg/kg (purple line). Tumors were harvested at indicated time points (n = 2–3 per time point). Values are plotted as mean ± SEM. B, PD in NCI-H2122 (KRASG12C/G12CSTK11mutKEAP1mut, NSCLC) subcutaneous xenograft tumors, shown as the relative change in human DUSP6 mRNA expression. Tumor-bearing mice were treated with a single dose (every day ×1, solid lines) or seven consecutive daily doses (every day ×7, dashed lines) of elironrasib at 100 mg/kg and daraxonrasib at 25 mg/kg as single agents or in combination. Tumors were harvested at indicated time points (n = 2–3 per time point). Data from elironrasib single agent, daraxonrasib single agent, and RAS(ON) inhibitor doublet groups are plotted in blue lines, green lines, and purple lines, respectively. Values are plotted as mean ± SEM. C and D, Histopathology analysis of NCI-H2122 subcutaneous xenograft tumors treated with a single dose (every day ×1, circles in the quantification plot) or seven consecutive daily doses (every day ×7, dots in the quantification plot) of elironrasib at 100 mg/kg and daraxonrasib at 25 mg/kg as single agents or in combination and collected at indicated time points (n = 3 per time point). C, Representative images are shown at 20× magnification from samples closest to the mean of the group. Tumors used for representative images of pERK, pS6, and Ki67 were collected at 48 hours after seven consecutive daily doses of RAS(ON) inhibitors. Tumors used for representative images of CC3 were collected at 24 hours after a single dose of RAS(ON) inhibitors. Scale bars, 100 μm. D, pERK, pS6, and CC3 staining in tumor areas and Ki67 staining in tumor cell nucleuses were quantified and compared with vehicle using one-way ANOVA followed by Dunnett multiple comparison test (*, P < 0.05; **, P < 0.01; ***, P < 0.001; ****, P < 0.0001). E, PD in CTG-2536 (KRASG12C/WT, HER2High, NSCLC) subcutaneous PDX tumors, shown as the relative change in human DUSP6 mRNA expression. Tumor-bearing mice were treated with a single dose of elironrasib at 200 mg/kg and daraxonrasib at 25 mg/kg as single agents or in combination. Tumors were harvested at indicated time points (n = 2–3 per time point). Data from elironrasib single agent, daraxonrasib single agent, and RAS(ON) inhibitor doublet groups are plotted in blue lines, green lines, and purple lines, respectively. Values are plotted as mean ± SEM. F, Histopathology analysis of CTG-2536 subcutaneous PDX tumors treated with a single dose of elironrasib at 200 mg/kg and daraxonrasib at 25 mg/kg as single agents or in combination and collected at indicated time points (n = 3 per time point). Representative images are shown at 20× magnification from samples closest to the mean of the group. Tumors used for representative images of pERK and CC3 were collected at 48 and 24 hours after a single dose of RAS(ON) inhibitors, respectively. Scale bars, 100 μm. po, orally; qd, every day.

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