Fig. 3: ULTR-p38i are effective in human CRC organoids and CRC mouse models.
a, Generation of patient-derived CRC organoids from primary or secondary tumor tissue upon surgery or paracentesis. b–f, Cell viability analysis in the patient-derived organoid cultures PDO1 (b), PDO2 (c), PDO3 (d), PDO4 (e) and PDO5 (f) upon 4 days of treatment with 1639, 2015, 2545 or DMSO (n = 3 biologically independent experiments; data are presented as the mean ± s.d.). Statistical significance was calculated using an ANOVA and Tukey’s multiple-comparisons test (P < 0.05). g, Selectivity profiling of 2015 in a panel of 340 kinases (Reaction Biology Europe, compound concentration = 1 µM and 0.2 µM). h,i, Experimental setup for treatment of KAP-shMapk14 and KAP-shNC organoids with 2015 or DMSO (h) and cell viability analysis (i) upon 6 days of treatment with doxycycline and 4 days of treatment with 2015 or DMSO (n = 3 biologically independent experiments; data are presented as the mean ± s.d.). Statistical significance was calculated using an ANOVA and Tukey’s multiple-comparisons test (P < 0.01). j, In vivo pharmacokinetic studies in mice treated with 2015 or 1639 (n = 3 mice per group; data are presented as the mean ± s.e.m.). k, Treatment of subcutaneous KAP tumors with 2015 in comparison to 1639 and carrier-treated tumors (Fig. 1j; n = 10 tumors per group; data are presented as the mean ± s.e.m.). Statistical significance was calculated using a two-tailed Student’s t-test (P < 0.0001). Treatment was started 1 week after organoid transplantation. The experiments in b–f and i were independently performed three times, with similar results.
