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NFE2L2 Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells.

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Mutations in NFE2L2 predict radioresistance in head and neck cancers. Activating these mutations increases resistance, but glutaminase inhibitor CB-839 can restore sensitivity to radiotherapy.

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Area of Science:

  • Oncology
  • Cancer Biology
  • Immunology

Background:

  • Head and neck squamous cell carcinoma (HNSCC) often recurs after radiotherapy.
  • Predictive biomarkers for radioresistance in HNSCC are lacking.
  • NFE2L2 mutations are implicated in cancer development and progression.

Purpose of the Study:

  • To investigate the role of NFE2L2 mutations in HNSCC radioresistance.
  • To identify potential therapeutic strategies to overcome NFE2L2-mediated radioresistance.

Main Methods:

  • Analysis of NFE2L2 mutation status in HNSCC patient cohorts.
  • In vivo and in vitro studies using HNSCC cell lines and mouse models.
  • Assessment of immune cell infiltration and cytokine expression.
  • Treatment with radiotherapy and the glutaminase inhibitor CB-839.

Main Results:

  • NFE2L2 mutations correlated with higher locoregional failure rates in HNSCC patients treated with adjuvant radiotherapy.
  • Mutant Nrf2 activated pathways leading to radioresistance by recruiting PMN-MDSC and reducing M1 macrophages.
  • CB-839 treatment overcame Nrf2-induced radioresistance and reversed immunosuppressive myeloid cell phenotypes.

Conclusions:

  • NFE2L2 mutations serve as predictive biomarkers for radioresistance in HNSCC.
  • Targeting glutaminase with CB-839 can enhance radiosensitivity in HNSCC with NFE2L2 mutations.
  • CB-839 shows potential for clinical application in combination with radiotherapy for HNSCC.