RT Journal Article
SR Electronic
T1 The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia
JF Clinical Cancer Research
JO Clin Cancer Res
FD American Association for Cancer Research
SP 5747
OP 5758
DO 10.1158/1078-0432.CCR-20-1315
VO 26
IS 21
A1 Verbeke, Delphine
A1 Demeyer, Sofie
A1 Prieto, Cristina
A1 de Bock, Charles E.
A1 De Bie, Jolien
A1 Gielen, Olga
A1 Jacobs, Kris
A1 Mentens, Nicole
A1 Verhoeven, Bronte Manouk
A1 Uyttebroeck, Anne
A1 Boeckx, Nancy
A1 De Keersmaecker, Kim
A1 Maertens, Johan
A1 Segers, Heidi
A1 Cools, Jan
YR 2020
UL http://clincancerres.aacrjournals.org/content/26/21/5747.abstract
AB Purpose: KPT-8602 (Eltanexor) is a second-generation exportin-1 (XPO1) inhibitor with potent activity against acute lymphoblastic leukemia (ALL) in preclinical models and with minimal effects on normal cells. In this study, we evaluated whether KPT-8602 would synergize with dexamethasone, vincristine, or doxorubicin, three drugs currently used for the treatment of ALL.Experimental Design: First, we searched for the most synergistic combination of KPT-8602 with dexamethasone, vincristine, or doxorubicin in vitro in both B-ALL and T-ALL cell lines using proliferation and apoptosis as a readout. Next, we validated this synergistic effect by treatment of clinically relevant B- and T-ALL patient-derived xenograft models in vivo. Finally, we performed RNA-sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) to determine the mechanism of synergy.Results: KPT-8602 showed strong synergism with dexamethasone on human B-ALL and T-ALL cell lines as well as in vivo in three patient-derived ALL xenografts. Compared with single-drug treatment, the drug combination caused increased apoptosis and led to histone depletion. Mechanistically, integration of ChIP-seq and RNA-seq data revealed that addition of KPT-8602 to dexamethasone enhanced the activity of the glucocorticoid receptor (NR3C1) and led to increased inhibition of E2F-mediated transcription. We observed strong inhibition of E2F target genes related to cell cycle, DNA replication, and transcriptional regulation.Conclusions: Our preclinical study demonstrates that KPT-8602 enhances the effects of dexamethasone to inhibit B-ALL and T-ALL cells via NR3C1- and E2F-mediated transcriptional complexes, allowing to achieve increased dexamethasone effects for patients.