Pre-clinical activity of a novel CRM1 inhibitor in acute myeloid leukemia
Menée in vitro et in vivo sur un modèle murin de leucémie myéloïde aiguë, cette étude évalue l'activité d'un composé appelé KPT-276, un nouvel inhibiteur du récepteur nucléaire CRM1
CRM1 is a nuclear export receptor involved in the active transport of tumor suppressors [e.g. p53 and nucleophosmin] whose function is altered in cancer due to increased expression and overactive transport. Blocking CRM1 mediated nuclear export of such proteins is a novel therapeutic strategy to restore tumor suppressor function. Orally bioavailable selective inhibitors of nuclear export (SINE) that irreversibly bind to CRM1 and block the function of this protein have been recently developed. Here, we investigated the anti-leukemic activity of KPT-SINE (KPT-185 and -276) in vitro and in vivo in acute myeloid leukemia (AML). KPT-185 displayed potent anti-proliferative properties at submicromolar concentrations (IC50 values; 100-500nM), induced apoptosis (average 5 fold increase), cell-cycle arrest and myeloid differentiation in AML cell lines and patient blasts. A strong down-regulation of the oncogene FLT3 after KPT treatment in both FLT3-ITD and wild type cell lines was observed. Finally, using the FLT3-ITD positive MV4-11 xenograft murine model, we show that treatment of mice with oral KPT-276 (analog of KPT-185 for in vivo studies) significantly prolongs survival of leukemic mice (P<0.01). In summary, KPT-SINEs are highly potent in vitro and in vivo in AML. The preclinical results reported here support clinical trials of KPT-SINE in AML.