Fig. 4: NOS inhibition augments PI3K inhibitor and taxane treatment in vivo. | Nature Communications

Fig. 4: NOS inhibition augments PI3K inhibitor and taxane treatment in vivo.

From: NOS inhibition sensitizes metaplastic breast cancer to PI3K inhibition and taxane therapy via c-JUN repression

Fig. 4

A Schematics representing the MpBC PDX (BCM-3807, BCM-4664, PIM-010, and PIM-084) experimental design. PDXs derived from human MpBCs were transplanted into cleared mammary fat-pad of female NSG mice. When tumors reached 150–200 mm3, mice were randomized to receive vehicle control, NOS inhibition therapy (L-NMMA [400 mg/kg oral gavage on day 1, 200 mg/kg oral gavage on days 2–5] + amlodipine [10 mg/kg intraperitoneal injection on days 1–5]), PI3K inhibitor alpelisib (35 mg/kg oral gavage on days 1–5), or the combination of both therapies as indicated. Caliper measurements were taken twice a week. Days in which mice were treated with therapies are indicated in red and rest days are indicated in green. B–E Mean tumor volume and corresponding waterfall plots demonstrating maximal treatment response to single-agent or combination therapy in four MpBC PDX models ([BCM-3807, n = 6], [PIM-010, n = 7], [PIM-084, n = 5], and [BCM-4664, n = 6]). Average tumor volume [0.5 × (mm long dimension) × (mm short dimension)2] and data points are mean tumor volume ± SEM. Statistical analysis for b–e by two-sided Student’s t test (*p ≤ 0.05, **p ≤ 0.01). Each bar in waterfall is derived from the maximal response of a single tumor-bearing mouse to therapy. Lines and bars in the plots indicated in black represent vehicle control, blue represent L-NMMA single-agent therapy, red represent alpelisib single-agent therapy, and gray indicate dual-agent therapy. P values: BCM-3807 (control vs L-NMMA+alpelisib [p = 0.0211], L-NMMA vs L-NMMA+alpelisib [p = 0.0398], alpelisib vs L-NMMA+alpelisib [p = 0.0456]), PIM-010 (control vs L-NMMA+alpelisib [p = 0.006], L-NMMA vs L-NMMA+alpelisib [p = 0.0231], alpelisib vs L-NMMA+alpelisib [p = 0.0079]), PIM-084 (control vs L-NMMA+alpelisib [p = 0.0231], alpelisib vs L-NMMA+alpelisib [p = 0.016]), BCM-4664 (control vs L-NMMA+alpelisib [p = 0.0052], L-NMMA vs L-NMMA+alpelisib [p = 0.0254], alpelisib vs L-NMMA+alpelisib [p = 0.1275]). F, G Tumor volumes of BCM-4664 (F) and BCM-3807 (G) tumors treated with vehicle control (black), docetaxel (purple), or combination therapy (docetaxel + NOS inhibition therapy [blue], docetaxel + alpelisib [green], and docetaxel + NOS inhibition therapy + alpelisib [red]). When tumors reached 150–200 mm3, they were randomized into the respective treatment arms. Each graph line represents a replicate/treatment arm. H, I Kaplan–Meier survival curves of model BCM-4664 (H) and BCM-3807 (I) treated with vehicle control, docetaxel, or combination therapy (dual/triple combination). An event was scored when a tumor reached 1200 mm3 or from death. Statistical analysis using Log-rank (Mantel–Cox) test. P values: BCM-4664 (docetaxel+alpelisib vs triple combination [p = 0.0432], docetaxel+L-NMMA vs triple combination [p = 0.0007], BCM-3807 (docetaxel vs. triple combination [p = 0.0192].

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