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Translational Cancer Mechanisms and Therapy

Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity

Marta Baro, Cecilia Lopez Sambrooks, Amanda Quijano, W. Mark Saltzman and Joseph Contessa
Marta Baro
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
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Cecilia Lopez Sambrooks
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.
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Amanda Quijano
Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
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W. Mark Saltzman
Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
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Joseph Contessa
Department of Therapeutic Radiology, Yale University, New Haven, Connecticut.Department of Pharmacology, Yale University, New Haven, Connecticut.
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  • For correspondence: joseph.contessa@yale.edu
DOI: 10.1158/1078-0432.CCR-18-0792 Published January 2019
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Abstract

Purpose: Parallel signaling reduces the effects of receptor tyrosine kinase (RTK)–targeted therapies in glioma. We hypothesized that inhibition of protein N-linked glycosylation, an endoplasmic reticulum co- and posttranslational modification crucial for RTK maturation and activation, could provide a new therapeutic approach for glioma radiosensitization.

Experimental Design: We investigated the effects of a small-molecule inhibitor of the oligosaccharyltransferase (NGI-1) on EGFR family receptors, MET, PDGFR, and FGFR1. The influence of glycosylation state on tumor cell radiosensitivity, chemotherapy-induced cell toxicity, DNA damage, and cell-cycle arrest were determined and correlated with glioma cell receptor expression profiles. The effects of NGI-1 on xenograft tumor growth were tested using a nanoparticle formulation validated by in vivo molecular imaging. A mechanistic role for RTK signaling was evaluated through the expression of a glycosylation-independent CD8-EGFR chimera.

Results: NGI-1 reduced glycosylation, protein levels, and activation of most RTKs. NGI-1 also enhanced the radiosensitivity and cytotoxic effects of chemotherapy in those glioma cells with elevated ErbB family activation, but not in cells without high levels of RTK activation. NGI-1 radiosensitization was associated with increases in both DNA damage and G1 cell-cycle arrest. Combined treatment of glioma xenografts with fractionated radiotherapy and NGI-1 significantly reduced tumor growth compared with controls. Expression of the CD8-EGFR eliminated the effects of NGI-1 on G1 arrest, DNA damage, and cellular radiosensitivity, identifying RTK inhibition as the principal mechanism for the NGI-1 effect.

Conclusions: This study suggests that oligosaccharyltransferase inhibition with NGI-1 is a novel approach to radiosensitize malignant gliomas with enhanced RTK signaling.

See related commentary by Wahl and Lawrence, p. 455

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Received March 9, 2018.
  • Revision received May 21, 2018.
  • Accepted June 27, 2018.
  • Published first July 2, 2018.
  • ©2018 American Association for Cancer Research.
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Clinical Cancer Research: 25 (2)
January 2019
Volume 25, Issue 2
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Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity
Marta Baro, Cecilia Lopez Sambrooks, Amanda Quijano, W. Mark Saltzman and Joseph Contessa
Clin Cancer Res January 15 2019 (25) (2) 784-795; DOI: 10.1158/1078-0432.CCR-18-0792

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Oligosaccharyltransferase Inhibition Reduces Receptor Tyrosine Kinase Activation and Enhances Glioma Radiosensitivity
Marta Baro, Cecilia Lopez Sambrooks, Amanda Quijano, W. Mark Saltzman and Joseph Contessa
Clin Cancer Res January 15 2019 (25) (2) 784-795; DOI: 10.1158/1078-0432.CCR-18-0792
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Clinical Cancer Research
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