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- W4361823318 abstract "<div>Abstract<p>Radiotherapy (RT) is one of the primary treatments of head and neck squamous cell carcinoma (HNSCC), which has a high-risk of locoregional failure (LRF). Presently, there is no reliable predictive biomarker of radioresistance in HNSCC. Here, we found that mutations in <i>NFE2L2</i>, which encodes Nrf2, are associated with a significantly higher rate of LRF in patients with oral cavity cancer treated with surgery and adjuvant (chemo)radiotherapy but not in those treated with surgery alone. Somatic mutation of <i>NFE2L2</i> led to Nrf2 activation and radioresistance in HNSCC cells. Tumors harboring mutant Nrf2<sup>E79Q</sup> were substantially more radioresistant than tumors with wild-type Nrf2 in immunocompetent mice, whereas the difference was diminished in immunocompromised mice. Nrf2<sup>E79Q</sup> enhanced radioresistance through increased recruitment of intratumoral polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) and reduction of M1-polarized macrophages. Treatment with the glutaminase inhibitor CB-839 overcame the radioresistance induced by Nrf2<sup>E79Q</sup> or Nrf2<sup>E79K</sup>. RT increased expression of PMN-MDSC–attracting chemokines, including CXCL1, CXLC3, and CSF3, in Nrf2<sup>E79Q</sup>-expressing tumors via the TLR4, which could be reversed by CB-839. This study provides insights into the impact of <i>NFE2L2</i> mutations on radioresistance and suggests that CB-839 can increase radiosensitivity by switching intratumoral myeloid cells to an antitumor phenotype, supporting clinical testing of CB-839 with RT in HNSCC with <i>NFE2L2</i> mutations.</p>Significance:<p><i>NFE2L2</i> mutations are predictive biomarkers of radioresistance in head and neck cancer and confer sensitivity to glutaminase inhibitors to overcome radioresistance.</p></div>" @default.
- W4361823318 created "2023-04-05" @default.
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- W4361823318 date "2023-03-31" @default.
- W4361823318 modified "2023-10-15" @default.
- W4361823318 title "Data from <i>NFE2L2</i> Mutations Enhance Radioresistance in Head and Neck Cancer by Modulating Intratumoral Myeloid Cells" @default.
- W4361823318 doi "https://doi.org/10.1158/0008-5472.c.6514371.v1" @default.
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