Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM

Matheson, E. C. et al. (2019) Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM. Haematologica, 104(9), pp. 1804-1811. (doi: 10.3324/haematol.2017.185975) (PMID:30655370) (PMCID:PMC6717586)

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Abstract

New drugs are needed for relapsed acute lymphoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown excellent activity in those with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorticoids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway mutated acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (CI <0.2; n=5). Associated pharmacodynamic assays were consistent with the hypothesis that the drug combination enhanced BIM upregulation over single drug alone. Dosing of dexamethasone and selumetinib singly, and in combination in mice engrafted with primary derived RAS pathway mutated leukemia cells, resulted in a marked reduction in spleen size which was significantly greater with the drug combination. Assessment of the central nervous system leukaemia burden showed a significant reduction in drug treated mice, with no detectable leukemia in those treated with the drug combination. These data suggest that a selumetinib-dexamethasone combination may be highly effective in RAS pathway mutated acute lymphoblastic leukemia and an international phase I/II clinical trial of dexamethasone and selumetinib (Seludex trial) is underway for children with multiple relapsed/refractory disease.

Item Type:Articles
Additional Information:The authors gratefully acknowledge Cancer Research UK (project grant to JAEI, HN and JV, number 18780), Bloodwise (previously known as the Leukaemia and Lymphoma Research Fund, project grant to JAEI, number 11007), the North of England Children’s Cancer Research Fund and the Newcastle Haematology Biobank for ALL samples.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halsey, Professor Chris
Authors: Matheson, E. C., Thomas, H., Case, M., Blair, H., Jackson, R. K., Masic, D., Veal, G., Halsey, C., Newell, D. R., Vormoor, J., and Irving, J. A.E.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Haematologica
Publisher:Ferrata Storti Foundation
ISSN:0390-6078
ISSN (Online):1592-8721
Published Online:17 January 2019
Copyright Holders:Copyright © 2019 Ferrata Storti Foundation
First Published:First published in Haematologica 104(9): 1804-1811
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
659581Identifying Novel Targets for eradication of acute lymphoblastic leukaemia in the central nervous systemChristina HalseyChief Scientist office (CSO)ETM/374III -IMMUNOLOGY