Fig. 10: KRASG12D inhibitor plus trastuzumab deruxtecan showed promising preclinical efficacy. | Nature Communications

Fig. 10: KRASG12D 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. 10

a Representative IF images showing increased surface and total HER2 expression (red) in Pa01c cells treated for 16 h with the indicated agents. LysoTracker Green DND-26 was used to stain the endolysosomes. (MRTX1133 0.5 μM, DS-8201a 0.1 μg/ml). Scale bars = 20 μM. b Representative FACS plots and quantification showing changes in surface (without cell permeabilization) and total (with cell permeabilization) HER2 abundance following 16 h treatment, as indicated in two different KRASG12D-mutant cell lines. (MRTX1133 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. Pa01c Surface HER2: MRTX1133 vs vehicle (p < 0.0001), DS-8201a vs vehicle (p < 0.0001), DS-8201a + MRTX1133 vs MRTX1133 (p < 0.0001) & DS-8201a + MRTX1133 vs DS-8201a (p = 0.1598), and Total HER2: MRTX1133 vs vehicle (p = 0.0008), DS-8201a vs vehicle (p < 0.0001), DS-8201a + MRTX1133 vs MRTX1133 (p < 0.0001) and DS-8201a + MRTX1133 vs DS-8201a (p = 0.1215). HPAC Surface HER2: MRTX1133 vs vehicle (p < 0.0001), DS-8201a vs vehicle (p < 0.0001), DS-8201a + MRTX1133 vs MRTX1133 (p < 0.0001) & DS-8201a + MRTX1133 vs DS-8201a (p = 0.1502), and Total HER2: MRTX1133 vs vehicle (p < 0.0001), DS-8201a vs vehicle (p = 0.0055), DS-8201a + MRTX1133 vs MRTX1133 (p < 0.0001) and DS-8201a + MRTX1133 vs DS-8201a (p = 0.1926). c Waterfall plot summarizing changes in tumour volume for each Pa01c tumour, as indicated. 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. P-values were calculated using one-way ANOVA followed by Tukey’s multiple comparison test. MRTX1133 vs vehicle (p < 0.0001), DS-8201a vs vehicle (p = 0.0001), DS-8201a + MRTX1133 vs vehicle (p < 0.0001), DS-8201a + MRTX1133 vs MRTX1133 (p = 0.0867) and DS-8201a + MRTX1133 vs DS-8201a (p = 0083). Source data are provided in Source Data file.

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