Figure 1 from Coordinated Targeting of S6K1/2 and AXL Disrupts Pyrimidine Biosynthesis in PTEN-Deficient Glioblastoma
Year: 2024
Type: other
Abstract: 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.
Authors: Catherine A. Behrmann, Kelli N. Ennis, Pranjal Sarma, Collin Wetzel, Nicholas A. Clark, Kate M. Von Handorf, Subrahmanya Vallabhapurapu, Cristina Andreani, James Reigle, Pier Paolo Scaglioni, Jarek Meller, Maria F. Czyzyk-Krzeska, Ady Kendler, Xiaoyang Qi, Jann N. Sarkaria, Mario Medvedovic, Soma Sengupta, Biplab Dasgupta, David R. Plas
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
OpenAlex ID: W4401823472