GSE135350
The XPO1 inhibitor KPT-8602 synergizes with dexamethasone for the inhibition of acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. Survival of ALL patients has improved significantly over the last 50 years. However, the current intensified chemotherapy is associated with serious short and long-term side effects in these young patients. Whereas KPT-8602 is a second generation exportin-1 (XPO-1) inhibitor with potent activity against ALL in pre-clinical models and with minimal effects on normal cells. In this study, we evaluated if synergistic ALL inhibition could be obtained by combining KPT-8602 with dexamethasone, vincristine or doxorubicin. Combination of KPT-8602 with dexamethasone showed the strongest synergistic effect on human B-ALL and T-ALL cell lines. This synergy was confirmed in vivo on three patient-derived ALL xenografts. Compared to single drug treatment, the drug combination caused increased apoptosis, reduced cell cycle gene expression and led to histone depletion. mRNA expression analysis and ChIP-seq revealed that addition of KPT-8602 to dexamethasone increased transcript level and binding of the glucocorticoid receptor, as well as NFKBIA expression. Dexamethasone concentrations could be reduced 5 to 10-fold in the presence of KPT-8602 to achieve the same level of NFKBIA induction as with dexamethasone alone. Our pre-clinical study demonstrates that combination of KPT-8602 and dexamethasone is highly synergistic in vivo. This opens the possibility to reduce dexamethasone concentrations and reduce side effects in future clinical trials. Overall design: RNA sequencing of ALL cell lines with different treatments: DMSO - dexamethasone (DEXA) - KPT-8602 (KPT) - combination of DEXA and KPT (COMBI) ChIPmentation sequencing of ALL cell lines with different treatments: DMSO - dexamethasone (DEXA) - KPT-8602 (KPT) - combination of DEXA and KPT (COMBI)