Fig. 4: Lack of wild-type Kras increases sensitivity to MEK inhibition in of KRASG12D colorectal tumours in vivo. | Nature Communications

Fig. 4: Lack of wild-type Kras increases sensitivity to MEK inhibition in of KRASG12D colorectal tumours in vivo.

From: KRAS allelic imbalance drives tumour initiation yet suppresses metastasis in colorectal cancer in vivo

Fig. 4

a Left, quantification of BrdU-positive cells per half crypt in Apcfl/fl Kras+/G12D and Apcfl/fl Krasfl/G12D mice 3 days post-induction treated with Vehicle or MEKi (AZD6244) as indicated (Apcfl/fl Kras+/G12D Vehicle, n = 5, 1M, 4F; MEKi, n = 4, 1M, 3F; and Apcfl/fl Krasfl/G12D Vehicle, n = 3, 1M, 2F; MEKi, n = 5, 3M, 2F). *P = 0.017. Right, representative H&E and BrdU images of Apcfl/fl Krasfl/G12D 3 days post-induction treated with Vehicle or MEKi (AZD6244) as indicated. Arrowheads show BrdU+ve hyper proliferative cells. Experiments carried out on C57BL/6J background ≥ N2. b Schematic presenting experimental approach. Apc+/fl Kras+/G12D and Apc+/fl Krasfl/G12D mice treated with MEKi one day post-induction and treated to clinical endpoint. Created with BioRender.com. c Kaplan–Meier survival curve of Apc+/fl Kras+/G12D and Apc+/fl Krasfl/G12D mice treated as shown in (b) aged until clinical endpoint (Apc+/fl Kras+/G12D, n = 8, 2M, 6F, MS, median survival = 72; Apc+/fl Kras+/G12D MEKi, n = 6, 2M, 4F, MS, median survival = 96; Apc+/fl Krasfl/G12D, n = 4, 2M, 2F, MS, median survival = 22; Apc+/fl Krasfl/G12D MEKi, n = 5, 4M, 1F, MS, median survival = 115). **P = 0.0050, ns not significant, log-rank (Mantel-Cox) test. d Boxplots showing total number of tumours from Apc+/fl Kras+/G12D and Apc+/fl Krasfl/G12D mice untreated or treated with MEKi as indicated in (c) and aged until clinical endpoint in SI and Colon (Apc+/fl Kras+/G12D, n = 8, 2M, 6F; Apc+/fl Kras+/G12D MEKi, n = 5, 2M, 3F; Apc+/fl Krasfl/G12D, n = 4, 2M, 2F; Apc+/fl Krasfl/G12D MEKi, n = 5, 4M, 1F). **P = 0.0079 (Apc+/fl Krasfl/G12D SI), *P = 0.0281, *P = 0.0397 (colon). e Left: Representative BrdU images of Apc+/fl Kras+/G12D and Apc+/fl Krasfl/G12D tumours from mice treated with MEKi from day 1 post-induction until clinical endpoint. Right: boxplot showing percentage of BrdU-positive tumour cells in Apc+/fl Kras+/G12D and Apc+/fl Krasfl/G12D treated with MEKi (Apc+/fl Kras+/G12D vehicle, n = 5, 1M, 2F; Apc+/fl Kras+/G12D MEKi, n = 5, 2M, 3F; Apc+/fl Krasfl/G12D untreated, n = 4, 2M, 2F; Apc+/fl Krasfl/G12D MEKi, n = 5, 4M, 1F), *P = 0.0159. a, d and e Boxes depict interquartile range, central line indicates median and whiskers indicate minimum/maximum values, one-way Mann–Whitney U test. Scale, 100 μm. Source data are provided as a Source Data file.

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