Fig. 6. Simultaneous Chk1 and DHODH inhibition sensitizes p53-deficient tumors to cell death and blocks metastases.

a FVB/N c-neu mice subcutaneously injected with syngeneic NeuTL cells (1 × 10⁶ cells per animal; 5 mice per group) and b FVB/N c-neu mice (three mice per group) with spontaneous tumors were treated intraperitoneally with LFM (20 mg/kg) alone or in combination with iChk1 (20 mg/kg)—see Methods for details. Tumor volumes were evaluated. c NSG mice were implanted with patient-derived xenografts (PDXs; four mice per group) from triple-negative wild type (WT) or mutated p53 (MUT) breast tumors and treated intraperitoneally with a combination of LFM (20 mg/kg) and iChk1 (20 mg/kg). d Balb/c mice injected with syngeneic 4T1 cells (10⁶ cells per animal; 5–6 mice per group) into mammary fat pad were treated intraperitoneally with LFM (20 mg/kg) alone or in combination with iChk1 (20 mg/kg)—see Methods for details. 4T1 cells circulating in blood or metastatic to lungs and liver were isolated and a number of 4T1 colonies was counted—see Methods for details. e Scheme of the mechanism of DHODH-induced cell cycle arrest. In a–d, data are shown as mean ± SEM. *P < 0.05, two-way ANOVA.