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. 2023 Sep 21;29(23):4870–4882. doi: 10.1158/1078-0432.CCR-23-1182

Figure 4.

Figure 4. Sensitivity to VEGFR-TKI and HC-5404 combination is independent of VHL mutation status. A and B, A-498 and Caki-1 RCC tumor xenografts treated with HC-5404 (30 mg/kg; orally, twice-a-day) and sunitinib (20 mg/kg; orally, once-a-day) for 30 days. Final tumor volume analyzed by Welch ANOVA or one-way ANOVA following homogeneity of variance tests. Data represent mean ± S.E.M., n = 10 mice per group (*, P < 0.05; ****, P < 0.001). C, pPERK and PERK abundance evaluated by SimpleWestern in RCC tumor xenografts treated for 7 days with HC-5404 (30 mg/kg; orally, twice-a-day), sunitinib (20 mg/kg in Caki-1 and A-498; 40 mg/kg in 786-O; orally, twice-a-day), or a combination thereof. D, Waterfall plot illustrating relative change in tumor volume of 18 diverse RCC PDX models following 28 days of treatment in a single animal (n = 1/group/model) with either axitinib (30 mg/kg; orally, twice-a-day), HC-5404 (30 mg/kg; orally, twice-a-day), or a combination thereof. Models ranked on % change tumor volume in combination group. PD = >30% increase from baseline; stable disease (SD) = ≤30% increase from baseline and <50% regression; PR = ≥50% regression. Models that are VHL WT are indicated by an arrow. E, Quantification of pPERK and PERK protein levels by SimpleWestern from pretreatment baseline PDX tumor samples. Y-axis represents arbitrary fluorescence units. Differences in pPERK/PERK levels evaluated by Student t test, *, P < 0.05 (VHL-WT n = 6; VHL-MUT n = 11). F, Final tumor volume of 18 RCC PDX models following 28 days of treatment with HC-5404 (30 mg/kg, orally, twice-a-day) and axitinib (30 mg/kg, orally, twice-a-day). Differences in tumor volume evaluated by Student t test; *, P < 0.05 (VHL-WT: n = 6; VHL-MUT: n = 12). G, RCC CDX tumor models treated with HC-5404 (30 mg/kg orally, twice-a-day) and DC-101 (15 mg/kg; i.p., twice a week) for 28 days. Tumor volume on day 28 (786-O, Caki-1) or day 21 (A-498) was analyzed by Welch ANOVA or one-way ANOVA following homogeneity of variance tests. Data represent mean ± S.E.M., n = 10 mice per group (*, P < 0.05; **, P < 0.01; ***, P < 0.005; ****, P < 0.001).

Sensitivity to VEGFR-TKI and HC-5404 combination is independent of VHL mutation status. A and B, A-498 and Caki-1 RCC tumor xenografts treated with HC-5404 (30 mg/kg; orally, twice-a-day) and sunitinib (20 mg/kg; orally, once-a-day) for 30 days. Final tumor volume analyzed by Welch ANOVA or one-way ANOVA following homogeneity of variance tests. Data represent mean ± S.E.M., n = 10 mice per group (*, P < 0.05; ****, P < 0.001). C, pPERK and PERK abundance evaluated by SimpleWestern in RCC tumor xenografts treated for 7 days with HC-5404 (30 mg/kg; orally, twice-a-day), sunitinib (20 mg/kg in Caki-1 and A-498; 40 mg/kg in 786-O; orally, twice-a-day), or a combination thereof. D, Waterfall plot illustrating relative change in tumor volume of 18 diverse RCC PDX models following 28 days of treatment in a single animal (n = 1/group/model) with either axitinib (30 mg/kg; orally, twice-a-day), HC-5404 (30 mg/kg; orally, twice-a-day), or a combination thereof. Models ranked on % change tumor volume in combination group. PD = >30% increase from baseline; stable disease (SD) = ≤30% increase from baseline and <50% regression; PR = ≥50% regression. Models that are VHL WT are indicated by an arrow. E, Quantification of pPERK and PERK protein levels by SimpleWestern from pretreatment baseline PDX tumor samples. Y-axis represents arbitrary fluorescence units. Differences in pPERK/PERK levels evaluated by Student t test, *, P < 0.05 (VHL-WT n = 6; VHL-MUT n = 11). F, Final tumor volume of 18 RCC PDX models following 28 days of treatment with HC-5404 (30 mg/kg, orally, twice-a-day) and axitinib (30 mg/kg, orally, twice-a-day). Differences in tumor volume evaluated by Student t test; *, P < 0.05 (VHL-WT: n = 6; VHL-MUT: n = 12). G, RCC CDX tumor models treated with HC-5404 (30 mg/kg orally, twice-a-day) and DC-101 (15 mg/kg; i.p., twice a week) for 28 days. Tumor volume on day 28 (786-O, Caki-1) or day 21 (A-498) was analyzed by Welch ANOVA or one-way ANOVA following homogeneity of variance tests. Data represent mean ± S.E.M., n = 10 mice per group (*, P < 0.05; **, P < 0.01; ***, P < 0.005; ****, P < 0.001).