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Translational Cancer Mechanisms and Therapy

The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia

Delphine Verbeke, Sofie Demeyer, Cristina Prieto, Charles E. de Bock, Jolien De Bie, Olga Gielen, Kris Jacobs, Nicole Mentens, Bronte Manouk Verhoeven, Anne Uyttebroeck, Nancy Boeckx, Kim De Keersmaecker, Johan Maertens, Heidi Segers and Jan Cools
Delphine Verbeke
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Sofie Demeyer
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Cristina Prieto
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Charles E. de Bock
4Children's Cancer Institute, Lowy Cancer Research Centre, University of New South Wales, Randwick, New South Wales, Australia.
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  • ORCID record for Charles E. de Bock
Jolien De Bie
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
5Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium.
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Olga Gielen
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Kris Jacobs
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Nicole Mentens
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Bronte Manouk Verhoeven
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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Anne Uyttebroeck
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
6Department of Pediatric Oncology, UZ Leuven, Leuven, Belgium.
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Nancy Boeckx
5Department of Laboratory Medicine, UZ Leuven, Leuven, Belgium.
7Department of Oncology, KU Leuven, Leuven, Belgium.
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Kim De Keersmaecker
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
7Department of Oncology, KU Leuven, Leuven, Belgium.
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Johan Maertens
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
8Department of Hematology, UZ Leuven, Leuven, Belgium.
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Heidi Segers
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
6Department of Pediatric Oncology, UZ Leuven, Leuven, Belgium.
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Jan Cools
1Center for Human Genetics, KU Leuven, Leuven, Belgium.
2Center for Cancer Biology, VIB, Leuven, Belgium.
3Leuvens Kanker Instituut (LKI), KU Leuven – UZ Leuven, Leuven, Belgium.
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  • ORCID record for Jan Cools
  • For correspondence: jan.cools@kuleuven.be
DOI: 10.1158/1078-0432.CCR-20-1315 Published November 2020
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Abstract

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.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • Clin Cancer Res 2020;26:5747–58

  • Received April 15, 2020.
  • Revision received July 20, 2020.
  • Accepted August 18, 2020.
  • Published first August 21, 2020.
  • ©2020 American Association for Cancer Research.
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Clinical Cancer Research: 26 (21)
November 2020
Volume 26, Issue 21
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The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia
Delphine Verbeke, Sofie Demeyer, Cristina Prieto, Charles E. de Bock, Jolien De Bie, Olga Gielen, Kris Jacobs, Nicole Mentens, Bronte Manouk Verhoeven, Anne Uyttebroeck, Nancy Boeckx, Kim De Keersmaecker, Johan Maertens, Heidi Segers and Jan Cools
Clin Cancer Res November 1 2020 (26) (21) 5747-5758; DOI: 10.1158/1078-0432.CCR-20-1315

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The XPO1 Inhibitor KPT-8602 Synergizes with Dexamethasone in Acute Lymphoblastic Leukemia
Delphine Verbeke, Sofie Demeyer, Cristina Prieto, Charles E. de Bock, Jolien De Bie, Olga Gielen, Kris Jacobs, Nicole Mentens, Bronte Manouk Verhoeven, Anne Uyttebroeck, Nancy Boeckx, Kim De Keersmaecker, Johan Maertens, Heidi Segers and Jan Cools
Clin Cancer Res November 1 2020 (26) (21) 5747-5758; DOI: 10.1158/1078-0432.CCR-20-1315
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