A5106113547- Phagocytosis and Immune Regulation
- PI3K/AKT/mTOR signaling in cancer
- Renal and related cancers
- Protein Degradation and Inhibitors
- Renal cell carcinoma treatment
- Pancreatic and Hepatic Oncology Research
- Cancer, Hypoxia, and Metabolism
University of Cincinnati Medical Center
2024
<p>GSEA, Kinativ</p>
<p>Tumor growth and body weight</p>
<p>Glucose flux</p>
<p>Gliomasphere drug responses</p>
Abstract Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and receptor tyrosine AXL using LY-2584702 BMS-777607 can overcome network redundancy reduce GBM tumor growth. This combination S6K1 suppressed glucose flux pyrimidine biosynthesis. Genetic inactivation studies map indicated both...
<div>Abstract<p>Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and receptor tyrosine AXL using LY-2584702 BMS-777607 can overcome network redundancy reduce GBM tumor growth. This combination S6K1 suppressed glucose flux pyrimidine biosynthesis. Genetic inactivation studies...
<p>Tumor growth and body weight</p>
<p>S6K2 and AXL have an effector—regulator relationship. <b>A,</b> GSEA identified response signature in RNA sequence analysis of sgS6K2 LN229 GBM cells. <b>B</b> <b>C,</b> sgNT or (exon 9) U87MG-GFP-Luc (<b>B</b>) (<b>C</b>) cells were stimulated with 300 nmol/L Phosphatidylserine (PtdSer) and/or 400 ng/mL Gas6 for 45 minutes as indicated. autophosphorylation pY702 was increased the absence S6K2. <b>D,</b> KiNativ...
<p>Glucose flux</p>
<p>PTEN-deficient patient-derived sphere growth is inhibited by combination S6K1 and AXL inhibition. <b>A,</b> JHH136 GBM were treated for 72 hours with 10 μmol/L LY-2584702 and/ or BMS-777607. Phase contrast images show reduced size inhibitor compared single treatment vehicle control (<i>n</i> = 3). Scale bar, 100 μm. <b>B,</b> Quantification of spheres in three independent cultures as <b>A</b> are shown. <i>P</i> values from...
<p>S6K1 and AXL inhibitors counteract pyrimidine biosynthesis in PTEN-deficient GBM. <b>A,</b> Steady state metabolite abundance LN229 GBM transfected with siPTEN then treated vehicle control or combination S6K1 (LY-2584702, 10 μmol/L) (BMS-777607, for 5 hours (<i>n</i> = 4). <b>B,</b> Detail of nucleotide their precursor metabolites from <b>A</b>. <b>C,</b> log<sub>2</sub> fold change...
<p>Targeting requirements in the S6K1/S6K2 network. <b>A</b> and <b>B,</b> S6 phosphorylation was reduced only upon genetic silencing of both S6K1 S6K2 LN229 GBM cells. <b>C,</b> Combined inactivation via sgRNA siRNA required to silence S6K signaling PTEN-deficient U87MG-GFP-Luc. <b>D,</b> DepMap correlation shows dependence on when PTEN is mutated. <b>E,</b> caused an induction seen as increase rpS6. This can be abrogated by...
<p>PTEN-deficient patient-derived sphere growth is inhibited by combination S6K1 and AXL inhibition. <b>A,</b> JHH136 GBM were treated for 72 hours with 10 μmol/L LY-2584702 and/ or BMS-777607. Phase contrast images show reduced size inhibitor compared single treatment vehicle control (<i>n</i> = 3). Scale bar, 100 μm. <b>B,</b> Quantification of spheres in three independent cultures as <b>A</b> are shown. <i>P</i> values from...
<div>Abstract<p>Intrinsic resistance to targeted therapeutics in PTEN-deficient glioblastoma (GBM) is mediated by redundant signaling networks that sustain critical metabolic functions. Here, we demonstrate coordinated inhibition of the ribosomal protein S6 kinase 1 (S6K1) and receptor tyrosine AXL using LY-2584702 BMS-777607 can overcome network redundancy reduce GBM tumor growth. This combination S6K1 suppressed glucose flux pyrimidine biosynthesis. Genetic inactivation studies...
<p>Tumor growth and body weight</p>