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Background <p>Extranodal NK/T-cell lymphoma (ENKTL) is a rare, aggressive lymphoma in which radioresistance remains a major cause of treatment failure in the relapsed/refractory (R/R) setting.</p> Methods <p>We analysed XPO1 expression in ENKTL and assessed its role in radiosensitization using monoallelic XPO1-knockout models and KPT-330 in vitro and in xenografts. Mechanistic studies focused on the c-Myc–RAD51/CHEK1 axis, and clinical efficacy was evaluated in two R/R patients.</p> Results <p>Immunohistochemistry showed XPO1 overexpression in primary treatment-naïve ENKTL specimens relative to nasal polyp controls, and high XPO1 expression was associated with inferior overall survival. Monoallelic XPO1 knockout impaired homologous recombination (HR) repair, establishing a DNA repair defect exploitable as a radiosensitizing vulnerability. Pharmacologic inhibition of XPO1 with KPT-330 recapitulated these HR defects and synergised with radiotherapy. Mechanistically, KPT-330 disrupts the XPO1–c-Myc–RAD51/CHEK1 axis by blocking c-Myc nuclear export, reducing c-Myc abundance and promoter occupancy at the RAD51 and CHEK1 loci, thereby impairing HR. In two heavily pretreated R/R ENKTL patients, radiotherapy rechallenge plus low-dose KPT-330 achieved one partial response and one complete response with manageable toxicity.</p> Conclusions <p>XPO1 inhibition impairs HR and enhances radiosensitivity by disrupting the c-Myc–RAD51/CHEK1 axis. These findings support prospective evaluation of KPT-330–based radiosensitization in R/R ENKTL.</p> <p></p>

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KPT-330-mediated XPO1 inhibition impairs homologous recombination and enhances radiosensitivity in extranodal NK/T-cell lymphoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月16日

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  • Huijie Zhou,
  • Qiuluo Liu,
  • Kexing Ren,
  • Qian Luo,
  • Chunli Yang,
  • Tian Fang,
  • Xi Chen,
  • Liqun Zou

摘要

Background

Extranodal NK/T-cell lymphoma (ENKTL) is a rare, aggressive lymphoma in which radioresistance remains a major cause of treatment failure in the relapsed/refractory (R/R) setting.

Methods

We analysed XPO1 expression in ENKTL and assessed its role in radiosensitization using monoallelic XPO1-knockout models and KPT-330 in vitro and in xenografts. Mechanistic studies focused on the c-Myc–RAD51/CHEK1 axis, and clinical efficacy was evaluated in two R/R patients.

Results

Immunohistochemistry showed XPO1 overexpression in primary treatment-naïve ENKTL specimens relative to nasal polyp controls, and high XPO1 expression was associated with inferior overall survival. Monoallelic XPO1 knockout impaired homologous recombination (HR) repair, establishing a DNA repair defect exploitable as a radiosensitizing vulnerability. Pharmacologic inhibition of XPO1 with KPT-330 recapitulated these HR defects and synergised with radiotherapy. Mechanistically, KPT-330 disrupts the XPO1–c-Myc–RAD51/CHEK1 axis by blocking c-Myc nuclear export, reducing c-Myc abundance and promoter occupancy at the RAD51 and CHEK1 loci, thereby impairing HR. In two heavily pretreated R/R ENKTL patients, radiotherapy rechallenge plus low-dose KPT-330 achieved one partial response and one complete response with manageable toxicity.

Conclusions

XPO1 inhibition impairs HR and enhances radiosensitivity by disrupting the c-Myc–RAD51/CHEK1 axis. These findings support prospective evaluation of KPT-330–based radiosensitization in R/R ENKTL.