Fig. 5.

(R)-crizotinib in combination with CDDP had synergistic antitumor effect on oncogene and carcinogen-induced lung cancer models. a–d Kras^LSL−G12D/+; Trp53^flox/flox (KP) mice were used as a conditional mouse model of NSCLC, tumor initiation and drug treatments were performed according to the scheme demonstrated in a. At the end of the experiment, all mice were euthanized and lungs were sampled to measure weight and subjected to further hematoxylin-eosin staining and immunohistochemistry. Representative hematoxylin-eosin stained lung lobes of KP mice that were treated with either solvent (Sol) or the combination of (R)-crizotinib (Criz) with cisplatin (CDDP) are shown in b. Lung weight was used as proxy of tumor burden and is depicted for tumor-free (Ctrl) and treated tumor-bearing mice (c). Hematoxylin-eosin based tumor area quantification on lung lobe sections of KP mice is presented (d). Results are expressed as mean ± s.e.m. *p < 0.05; ***p < 0.001 as compared to Sol, ^#p < 0.05 as comparing indicated groups using Student’s t-test, n = minimum of 6 mice per group. Friend Virus B (FVB) mice were used as a spontaneous mouse model of lung adenocarcinoma, tumor induction and drug treatments were performed according to the scheme demonstrated in e. Tumor development was monitored with microCT photographing and all mice were euthanized to obtain lung lobes for further histology. Representative stereo microscope scans of lung lobes (f), as well as quantified neoplasia numbers (g, h) and tumor sizes (i) are reported. Results are expressed as mean ± s.e.m. **p < 0.01; ***p < 0.001 as compared to Sol, ^##p < 0.01 as comparing neoplasia numbers in specific size using Student’s t-test, scale bar equals 1 mm, n = minimum of 9 mice per group