Fig. 9: KRASG12C inhibitor plus trastuzumab deruxtecan showed promising preclinical efficacy. | Nature Communications

Fig. 9: KRASG12C inhibitor plus trastuzumab deruxtecan showed promising preclinical efficacy.

From: Combined KRAS-MAPK pathway inhibitors and HER2-directed drug conjugate is efficacious in pancreatic cancer

Fig. 9

a Representative FACS plots and quantification showing changes in surface and total HER2 abundance following 16 h treatment, as indicated in three different KRASG12C-mutant cell lines. (AMG-510 0.5 μM, DS-8201a 0.1 μg/ml). Data represents one of three independent experiments each done in triplicates. Data are presented as the mean ± SEM. P-values were calculated using one way ANOVA followed by Tukey’s multiple comparisons test. NCL-H2122 Surface HER2 (AMG-510 vs vehicle: p < 0.0001, DS-8201a vs vehicle: p < 0.0001, DS-8201a + AMG-510 vs AMG-510: p < 0.0001 & DS-8201a + AMG-510 vs DS-8201a: p = 0.0120), and Total HER2 (AMG-510 vs vehicle: p = 0004, DS-8201a vs vehicle: p < 0.0001, DS-8201a + AMG-510 vs AMG-510: p < 0.0001 and DS-8201a + AMG-510 vs DS-8201a: p = 0.8964); NCL-H2030 Surface HER2 (AMG-510 vs vehicle: p = 0.0006, DS-8201a vs vehicle: p < 0.0001, DS-8201a + AMG-510 vs AMG-510: p < 0.0001 & DS-8201a + AMG-510 vs DS-8201a: p = 0041), and Total HER2 (AMG-510 vs vehicle: p = 0.3401, DS-8201a vs vehicle: p < 0.0001, DS-8201a + AMG-510 vs AMG-510: p < 0.0001 and DS-8201a + AMG-510 vs DS-8201a: p = 0.9033; MIA Paca-2 Surface HER2 (AMG-510 vs vehicle: p = 0.0047, DS-8201a vs vehicle: p < 0.0001, DS-8201a + AMG-510 vs AMG-510: p < 0.0001 & DS-8201a + AMG-510 vs DS-8201a: p = 0.2871), and Total HER2 (AMG-510 vs vehicle: p = 0.0030, DS-8201a vs vehicle: p < 0.0001, DS-8201a + AMG-510 vs AMG-510: p < 0.0001 and DS-8201a + AMG-510 vs DS-8201a: p = 0.9985). b Median effect analyses of AMG-510 in combination with DS-8201a in three KRASG12C-mutant cell lines, as represented by combination indices (CI) calculated using Compusyn software. Cells were cultured in triplicate at six fixed-ratio concentrations (1:1, 0.5:0.5, 0.25:0.25, 0.125:0.125, 0.063:0.063, and 0.031:0.031) for 3 days, and viability was measured using the Alamar Blue assay. c Waterfall plot summarizing changes in tumour volume for each MIA Paca-2 tumour. All mice were euthanized simultaneously when vehicle-treated mice reached the humane endpoints, and comparison to the baseline was made. The treatment response was determined using the clinical RECIST 1.1 criteria. Each bar represents an individual tumour. N = 7/arm. P-values were calculated using one-way ANOVA followed by Tukey’s multiple comparison test. AMG-510 vs vehicle (p = 0.0007), DS-8201a vs vehicle (p = 0.0002), DS-8201a + AMG-510 vs vehicle (p < 0.0001), DS-8201a + AMG-510 vs DS-8201a (p = 0084) and DS-8201a + AMG-510 vs DS-8201a (p = 0022).

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