Figure 1 from Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma

Combination S6K1 and AXL targeting reduces PTEN-deficient glioblastoma tumors in vivo. A, Combination S6K1 and AXL inhibitors, LY-2584702 and BMS-777607, respectively, reduced subcutaneous tumor volumes. Nude mice were implanted with 1 million U87MG cells and then treated twice daily (BID) with inhibitors by oral gavage on a 5 + 2 schedule. Animals were euthanized once tumors measured 2,000 mm³. B, Brain lysates from NSG mice treated with 30 mg/kg of LY-2584702, 30 mg/kg of BMS-777607, a combination of LY + BMS, or DMSO for 3 days BID. Reduced rpS6 phosphorylation was detected in intact brains collected an hour after final dose. C, In a time course of combination treatment, rpS6 phosphorylation was reduced in B6 mouse intact brain lysates as early as 30 minutes after final treatment. LY-2584702 and BMS-777607 reduced rpS6 phosphorylation in the brain, even in the absence of tumor. D, The S6K1 inhibitor, LY-2584702, in combination with the AXL inhibitor, BMS-777607, reduced tumor growth in orthotopically implanted U87MG-GFP-Luciferase cells. Growth of intracranial tumors was determined from bioluminescence imaging before treatment began and again after a month of BID 5 + 2 oral gavage inhibitors (12.5 mg/kg) or vehicle control (n = 5). E, Tumor growth of D shown as the change in luciferase counts from pretreatment to 32 days after treatment initiation. P value = 0.015 (t test). F, Histological staining of phospho-rpS6 (S235/6) of tumor sections from whole excised brains of mice treated with DMSO or LY + BMS combination. The staining intensity of these samples were graded 1–3 in a blinded fashion. Scale bar, 200 μm.