Figure 3. IMPDH dependence is a generalizable metabolic liability in MYC-driven tumors.

(A) Upper left, MPA IC₅₀ in 8 ASCL1^hi and 6 ASCL1^lo cell lines. Others, IC₅₀ of MPA and cisplatin in treatment-naive and chemoresistant pairs. *P < 0.05, **P < 0.01, ***P < 0.001. (B) Xenograft growth, displaying mean and SD for tumor volume (n = 5 mice per group). Arrows indicate start of treatment. ****P < 0.0001. (C) Treatment-naive H1436 xenograft growth. Four cycles of cisplatin (5 mg/kg/w) and etoposide (10 mg/kg/w, EC), or mizoribine (100 mg/kg/d) were administered, starting at the arrow. Individual volumes are displayed. **P < 0.01, ****P < 0.0001. (D and E) H1436 tumors pretreated with cisplatin and etoposide in C, then implanted into new mice. The arrow indicates start of treatment. Individual volumes are displayed. **P < 0.01, ****P < 0.0001. (F) mRNA abundance in parental (P) and chemoresistant (CR) H1436 tumors. Individual data points are shown with mean and SD for 3 replicates of 4 tumors from each group. **P < 0.01, ****P < 0.0001. (G) Survival analysis of LAP-MYC mice treated with saline or mizoribine (n = 12 per group). Dosing began on day 26 after birth (arrow). ****P < 0.0001. (H) Abdominal circumference of LAP-MYC mice treated with saline or mizoribine. Measurements were taken on day 42. ***P < 0.001. (I) Livers of LAP-MYC mice treated with saline or mizoribine. Dissections were performed on day 42. Statistical significance was assessed using a 2-tailed Student’s t test (A, F, and H), 2-way ANOVA with Tukey’s multiple comparisons (B–E), log-rank (Mantel-Cox) test (G). In panels C–E, individual tumors are displayed to demonstrate variability, but statistical comparisons were made with the average and standard error among the groups. Mizoribine treatment of LAP-MYC mice was performed once. All other experiments were repeated twice or more.