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)

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 > School 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

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
190794		Identifying Novel Targets for eradication of acute lymphoblastic leukaemia in the central nervous system	Christina Halsey	Chief Scientist Office (CSO)	ETM/374	III - Immunology