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

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.