Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia

Shi, Y. et al. (2021) Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia. Haematologica, 106(4), pp. 1056-1066. (doi: 10.3324/haematol.2019.241026) (PMID:32139432) (PMCID:PMC8018112)

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Abstract

T-cell Acute Lymphoblastic Leukemia (T-ALL) is frequently characterized by glucocorticoid (GC) resistance, which is associated with inferior outcomes, thus highlighting the need for novel therapeutic approaches for GC resistant T-ALL. The pTCR/TCR signaling pathways play a critical role in cell fate decisions during physiological thymocyte development, with an interplay between TCR and glucocorticoid receptor (GR) signaling determining the T-lymphocyte selection process. We performed an shRNA screen in vitro and in vivo in T-ALL cell lines and patient derived xenograft (PDX) samples to identify vulnerabilities in the pTCR/TCR pathway and identified a critical role for the kinase LCK in cell proliferation. LCK knockdown or inhibition with dasatinib (DAS) caused cell cycle arrest. Combination of DAS with dexamethasone (DEX) resulted in significant drug synergy leading to cell death. The efficacy of this drug combination was underscored in a randomized phase II-like murine trial, recapitulating an early phase human clinical trial. T-ALL expansion in immunocompromised mice was significantly impaired using this drug combination, relative to mice receiving control vehicle or single drug treatment, highlighting the immediate clinical relevance of this drug combination for high risk T-ALL patients. Our results thus provide a strategy to improve the efficacy of current chemotherapy platforms and circumvent GC resistance.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Halsey, Professor Chris
Authors: Shi, Y., Beckett, M. C., Blair, H. J., Tirtakusuma, R., Nakjang, S., Enshaei, A., Halsey, C., Vormoor, J., Heidenreich, O., Krippner-Heidenreich, A., and van Delft, F. W.
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:05 March 2020
Copyright Holders:Copyright © 2021 Ferrata Storti Foundation
First Published:First published in Haematologica 106(4): 1056-1066
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
190794Identifying Novel Targets for eradication of acute lymphoblastic leukaemia in the central nervous systemChristina HalseyChief Scientist Office (CSO)ETM/374III - Immunology