Data from Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity

• DOI: 10.1158/1078-0432.c.6528881
• Publication Date: 2023-04-01T09:05:09Z
• Authors: Marta Baro; Cecilia Lopez Sam...; Amanda Quijano; W. Mark Saltzman; Joseph Contessa
• Keywords: Radiosensitivity

<div>AbstractPurpose:<p>Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation activation, could provide a new therapeutic approach glioma radiosensitization.</p><p><b>Experimental Design:</b> investigated small-molecule inhibitor oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, FGFR1. The influence glycosylation state tumor cell radiosensitivity, chemotherapy-induced toxicity, DNA damage, cell-cycle arrest were determined correlated with expression profiles. NGI-1 xenograft growth tested using nanoparticle formulation validated by <i>in vivo</i> molecular imaging. A mechanistic role was evaluated through glycosylation-independent CD8-EGFR chimera.</p>Results:<p>NGI-1 reduced levels, activation most RTKs. also enhanced radiosensitivity cytotoxic chemotherapy those cells elevated ErbB but not without high levels activation. radiosensitization associated increases both damage G<sub>1</sub> arrest. Combined treatment xenografts fractionated radiotherapy significantly compared controls. Expression eliminated arrest, cellular identifying as principal mechanism effect.</p>Conclusions:<p>This study suggests is novel to radiosensitize malignant gliomas signaling.</p><p><i>See related commentary Wahl Lawrence, p. 455</i></p></div>