Page 140 - 2021_04-Haematologica-web

Ferrata Storti Foundation
Haematologica 2021 Volume 106(4):1056-1066
Acute Lymphoblastic Leukemia
Phase II-like murine trial identifies synergy between dexamethasone and dasatinib in T-cell acute lymphoblastic leukemia
Yuzhe Shi,1 Melanie C. Beckett,1 Helen J. Blair,1 Ricky Tirtakusuma,1
Sirintra Nakjang,1 Amir Enshaei,1 Christina Halsey,2 Josef Vormoor,3
Olaf Heidenreich,1,3 Anja Krippner-Heidenreich3# and Frederik W. van Delft1#
1Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK; 2Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University
3
ofGlasgow,Glasgow,UKand PrinsesMáximaCentrumvoorKinderoncologie,Utrecht,
the Netherlands
#AKH and FWvD contributed equally as co-senior authors.
ABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is frequently character- ized by glucocorticoid (GC) resistance, which is associated with infe- rior outcomes, thus highlighting the need for novel therapeutic approaches for GC-resistant T-ALL. The pre-T-cell receptor (pTCR)/TCR signaling pathways play a critical role in cell fate decisions during physio- logical thymocyte development, with an interplay between TCR and glu- cocorticoid 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 lymphocyte cell-specific 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 random- ized 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, compared to mice receiving control vehicle or single drug treatment, highlighting the immediate clinical rele- vance 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.
Introduction
Current minimal residual disease (MRD)-stratified chemotherapy protocols for patients with T-cell acute lymphoblastic leukemia (T-ALL) result in 5-year event- free survival rates of 80% and 50% for pediatric and adult patients, respectively.1,2 Induction failure, early relapse, and isolated central nervous system (CNS) involve- ment are more common in T- than B-lineage ALL.3 Moreover, resistance to conven- tional chemotherapy including glucocorticoid (GC) is a frequent feature of relapsed and refractory T-ALL, reducing the second remission rate and long-term outcomes.4 GC are an instrumental component of ALL therapy and induce apoptosis in lym- phoid malignancies.5-7 Resistance to GC is a critical factor influencing treatment response and outcome.5,8-11 Amongst ALL subtypes, GC resistance is more frequent- ly observed in infant ALL and T-ALL.5,9,11,12
Endogenous GC can induce apoptosis during the selection process of T lympho- cytes in the thymus, an effect which can be constrained by crosstalk with T-cell receptor (TCR) signaling.13,14 Whilst mature T-cell maintenance requires tonic TCR signaling, inappropriate TCR expression has been shown to give rise to T-cell malignancies in mouse model systems.15,16
The immature pre-T-cell receptor (pTCR) consists of a complex of alpha (pTCRα) and beta (TCRβ) peptide chains complexed with CD3de and CD3γe heterodimers.
Correspondence:
FREDERIK W. VAN DELFT
frederik.van-delft@newcastle.ac.uk
Received: October 21, 2019. Accepted: March 4, 2020. Pre-published: March 5, 2020.
https://doi.org/10.3324/haematol.2019.241026
©2021 Ferrata Storti Foundation
Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or inter- nal use. Sharing published material for non-commercial pur- poses is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for com- mercial purposes is not allowed without permission in writing from the publisher.
1056
haematologica | 2021; 106(4)
ARTICLE