KPT-330-mediated XPO1 inhibition impairs homologous recombination and enhances radiosensitivity in extranodal NK/T-cell lymphoma
Menée à l'aide de lignées cellulaires et de xénogreffes de lymphome extra-ganglionnaire à cellules T ou NK sur des modèles murins, cette étude met en évidence un mécanisme par lequel l'inhibition de l'expression de l'exportine XPO1 altère le système de réparation homologue de l'ADN et augmente la radiosensibilité des cellules cancéreuses en affectant l'axe c-Myc–RAD51/CHEK1
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.
British Journal of Cancer , article en libre accès, 2026