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 |
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| 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 > School 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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