Figure 7.
Phendione inhibits growth of human tumors with BRAF or NRAS mutations and overcomes resistance to BRAF inhibition in vivo. (A,B) Tumor volume of BRAFV600E PDXs treated with BRAFi (dabrafenib) at 30 mg/kg daily by oral gavage, or phendione at 5 mg/kg every 2 d intraperitoneally (i.p.); vehicle was used as control in A. Zoomed-in curves of BRAFi and phendione treatments are shown in B. Data are mean ± SEM, n = 5. (****) P < 0.0001, by two-way ANOVA with Tukey's multiple comparisons test. Dotted line in A and B indicates the tumor volume on the day of treatment started. (C,D) Dot plots of BRAFV600E PDX tumor volume (C) and weight (D) at day 21. Data are mean ± SEM. (*) P < 0.05; (***) P < 0.001; (****) P < 0.0001, by unpaired two-tailed Student's t-test. (E) Representative images of immunohistochemistry staining with antibody against phospho-ATM (S1981) for BRAFV600E PDXs treated as indicated. (F) Tumor volume of NRASQ61R PDXs treated with phendione at 5 mg/kg every 2 d intraperitoneally (i.p.), or with vehicle. Data are mean ± SEM, n = 9. (****) P < 0.0001, by two-way ANOVA with Tukey's multiple comparisons test. (G,H) Dot plots of NRASQ61R tumor volume (G) and weight (H) at day 15. Data are mean ± SEM. (*) P < 0.05; (****) P < 0.0001, by unpaired two-tailed Student's t-test. (I) Representative images of immunohistochemistry staining with antibody against phospho-ATM (S1981) for NRASQ61R PDXs after indicated treatments. (J) Phendione prevents tumor relapse in BRAFV600E PDX model. Data are mean ± SEM, n = 7. (****) P < 0.0001, by two-way ANOVA with Tukey's multiple comparisons test. (K,L) Dot plots of tumor volume (K) and weight (L) of BRAFV600E PDXs. Data are mean ± SEM. (*) P < 0.05; (**) P < 0.01, by unpaired two-tailed Student's t-test. (M) Representative images of immunohistochemistry staining with antibody against phospho-ATM (S1981) of BRAFV600E PDXs treated as indicated. Scale bars, 25 µm.