Figure 5 from Small-Molecule Polθ Inhibitors Provide Safe and Effective Tumor Radiosensitization in Preclinical Models
Rodriguez-Berriguete G., Ranzani M., Prevo R., Puliyadi R., Machado N., Bolland HR., Millar V., Ebner D., Boursier M., Cerutti A., Cicconi A., Galbiati A., Grande D., Grinkevich V., Majithiya JB., Piscitello D., Rajendra E., Stockley ML., Boulton SJ., Hammond EM., Heald RA., Smith GCM., Robinson HMR., Higgins GS.
<p>Polθ inhibitor ART899 combined with radiation causes significant tumor growth delay <i>in vivo</i> and is well tolerated. <b>A,</b> ART899 plasma concentration following oral dosage of ART899 at 50 or 150 mg/kg. Mouse plasma samples (<i>n</i> = 3 per treatment group) were collected at 30 minutes, 1, 2, 4, 8, and 12 hours after last dose. <b>B–E,</b> HCT116 tumor-bearing mice treated with 150 mg/kg Polθ inhibitor ART899 twice daily for 12 days and/or 10 × 2 Gy (days 1–5 and 8–12). Vehicle (<i>n</i> = 9); ART899 (<i>n</i> = 10); 10 × 2 Gy + vehicle (<i>n</i> = 10); 10 × 2 Gy + ART899 (<i>n</i> = 10). <b>B,</b> Mean ± SEM relative tumor size. <i>P</i> value from mixed effect model and Dunnett post-test. Comparison of tumor size at the latest common timepoint for 10 × 2 Gy versus 10 × 2 Gy + ART899 are shown in Supplementary Fig. S6A. <b>C,</b> Individual mouse graphs. <b>D,</b> Kaplan–Meier plot for a tumor size threshold of 1,000 mm<sup>3</sup>. HR: Hazard ratio (hazard rate of IR arm / hazard rate of IR + ART899 arm); <i>P</i> value from the log-rank (Mantel-Cox) test comparing IR alone and IR + ART558. The median time to a tumor size of 1,000 mm<sup>3</sup> for the IR + ART899 arm versus the IR arm and the corresponding ratio are shown in Supplementary Fig. S6B. <b>E,</b> Average mouse weight ± SD from all treatment groups over time. Individual mouse weights are shown in Supplementary Fig. S6C.</p>