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Ferrata Storti Foundation
Haematologica 2019 Volume 104(9):1804-1811
Acute Lymphoblastic Leukemia
Glucocorticoids and selumetinib are highly synergistic in RAS pathway-mutated childhood acute lymphoblastic leukemia through upregulation of BIM
Elizabeth C. Matheson,1 Huw Thomas,1 Marian Case,1 Helen Blair,1 Rosanna K. Jackson,1 Dino Masic,1 Gareth Veal,1 Chris Halsey,2 David R. Newell,1 Josef Vormoor1,3 and Julie A.E. Irving1
1Newcastle Cancer Centre at the Northern Institute for Cancer Research, Newcastle
2
University, Newcastle upon Tyne; Wolfson Wohl Cancer Research Centre, Institute of
Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow and 3Great North Children’s Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
ABSTRACT
New drugs are needed for the treatment of relapsed acute lym- phoblastic leukemia and preclinical evaluation of the MEK inhibitor, selumetinib, has shown that this drug has excellent activity in those leukemias with RAS pathway mutations. The proapoptotic protein, BIM is pivotal in the induction of cell death by both selumetinib and glucocorti- coids, suggesting the potential for synergy. Thus, combination indices for dexamethasone and selumetinib were determined in RAS pathway-mutat- ed acute lymphoblastic leukemia primagraft cells in vitro and were indicative of strong synergism (combination index <0.2; n=5). Associated pharmaco- dynamic assays were consistent with the hypothesis that the drug combi- nation enhanced BIM upregulation over that achieved by a single drug alone. Dosing of dexamethasone and selumetinib singly and in combina- tion in mice engrafted with primary-derived RAS pathway-mutated leukemia cells resulted in a marked reduction in spleen size which was sig- nificantly greater with the drug combination. Assessment of the central nervous system leukemia burden showed a significant reduction in the 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 lym- phoblastic leukemia. An international phase I/II clinical trial of dexametha- sone and selumetinib (Seludex trial) is underway in children with multiply relapsed/refractory disease.
Introduction
Progress in the treatment of childhood acute lymphoblastic leukemia has been exceptional and, using contemporary regimens, sustained remission is achievable in almost 90% of children.1,2 However, the outcome of children who relapse is much poorer and remains a frequent cause of death in children with cancer.3-5 Since further intensification with traditional agents is often associated with significant toxicity and limited success, new therapies are clearly needed. One promising avenue that may deliver novel drugs comes from our previous work showing that mutation in genes which activate the Ras/Raf/Mek/Erk pathway, such as NRAS, KRAS, FLT3, and PTPN11, are highly prevalent in relapsed ALL and, importantly, mutated ALL cells are differentially sensitive to the MEK inhibitor, selumetinib (AZD6244, ARRY-142886).6-8 In contrast, RAS pathway wildtype ALL cells were insensitive to MEK inhibition, both in vitro and in vivo.6 In the IBFMREZ2002 clinical trial for relapsed ALL, RAS pathway mutations were associated with high-risk fea- tures such as early relapse, central nervous system (CNS) disease and chemo-resis- tance and a poorer overall survival was seen in patients with KRAS mutations.6 In
Correspondence:
JULIE IRVING
j.a.e.irving@ncl.ac.uk
Received: March 16, 2018. Accepted: January 15, 2019. Pre-published: January17,2019.
doi:10.3324/haematol.2017.185975
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/104/9/1804
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