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

Lookup NU author(s): Yuzhe Shi, Melanie Beckett, Dr Helen Blair, Dr Ricky Tirtakusuma, Dr Sirintra Nakjang, Dr Amir EnshaeiORCiD, Dr Frederik van DelftORCiD

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).

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.

Publication metadata

Author(s): Shi Y, Beckett MC, Blair HJ, Tirtakusuma R, Nakjang S, Enshaei A, Halsey C, Vormoor J, Heidenreich O, Krippner-Heidenreich A, van Delft FW

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2021

Volume: 106

Issue: 4

Pages: 1056-1066

Print publication date: 01/04/2021

Online publication date: 05/03/2020

Acceptance date: 04/03/2020

Date deposited: 22/04/2020

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Fondazione Ferrata Storti

URL: https://doi.org/10.3324/haematol.2019.241026

DOI: 10.3324/haematol.2019.241026

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