Fig. 4. RMC-7977 can overcome resistance to mutant-selective KRAS inhibition.
a, Western blots showing the time course of RAS signalling in KRASG12D PDAC cell lines treated with RMC-7977, MRTX1133 or DMSO control. Total ERK and vinculin were used as loading controls. Data are representative of two similar experiments. b,c, Parental NCI-H358 cells (KRASG12C, NSCLC) (b) and adagrasib-resistant NCI-H358 cells with a secondary NRASQ61K mutation (c) were treated with adagrasib or RMC-7977 for 5 days and proliferation was measured by CTG assay. d,e, NCI-H358 (KRASG12C, NSCLC) cells expressing exogenous RTK DNA constructs as indicated (GFP control, wild-type EGFR, EGFR(A289V), HER2, FGFR2 or RET(M918T)) were treated with adagrasib (d) or RMC-7977 (e) for 120 h, and proliferation was measured by CTG assay. f,g, MIA PaCa-2 (KRASG12C, PDAC) cells expressing exogenous RTK fusion DNA constructs as indicated (GFP control, EML4–ALK, CCDC6–RET or FGFR3–TACC3) were treated with adagrasib (f) or RMC-7977 (g) for 120 h, and proliferation was measured by CTG assay. d–g, Biological duplicates normalized to vehicle control are shown from one of 2–5 independent experiments. h, Patient-derived xenograft model established from a patient with KRASG12C NSCLC who developed resistance after sotorasib. Mice were treated with vehicle (n = 7), sotorasib (50 mg kg−1 orally once daily; n = 7), or RMC-7977 (10 mg kg−1 orally once daily; n = 10). Tumour volumes were assessed for 17 days after treatment started. ***Adjusted P value = 0.0001 for RMC-7977 versus control group; repeated measures two-way ANOVA adjusted based on multiple comparison via Dunnett’s test on the final tumour measurement. Data are mean ± s.e.m. n refers to the number of mice in each group.