Klin Padiatr 2019; 231(03): 166
DOI: 10.1055/s-0039-1687164
Abstracts
Georg Thieme Verlag KG Stuttgart · New York

Dasatinib and Dexamethasone offer a novel therapeutic strategy for T-cell Acute Lymphoblastic Leukaemia

Y Shi
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
M Beckett
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
H Blair
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
R Tirtakusuma
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
S Nakjang
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
A Enshaei
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
,
O Heidenreich
2   Princess M'axima Center for Pediatric Oncology, Utrecht, The Netherlands
,
A Krippner-Heidenreich
2   Princess M'axima Center for Pediatric Oncology, Utrecht, The Netherlands
,
F Van Delft
1   Wolfson Childhood Cancer Research Centre, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
› Author Affiliations
Further Information

Publication History

Publication Date:
20 May 2019 (online)

 

T-cell Acute Lymphoblastic Leukaemia (T-ALL) is caused by malignant transformation of T cells showing differentiation arrest and uncontrolled proliferation. The checkpoints during T-cell development are dominated by pre-T-cell receptor (pTCR) for β-selection and T-cell receptor (TCR) for positive/negative selection. LCK is a central molecule in pTCR/TCR signalling transduction. To investigate the importance of pTCR/TCR complex for T-ALL cell proliferation and survival, a targeted in vitro and in vivo shRNA screen in 4 cell lines and 2 PDXs identified LCK to be crucial for T-ALL maintenance and engraftment. Mechanistic analyses indicate that knockdown or inhibition of LCK by Dasatinib impairs cell proliferation by inducing G1/G0 arrest. Moreover, LCK knockdown significantly sensitises cells to Dexamethasone (Dex), and strong synergistic lethal effects between Dex and Dasatinib have been observed in various cell lines and PDXs. A randomised phase II-like trial in NSG mice demonstrates a significant reduction in leukaemia burden after combination treatment. The Dex/Dasatinib combination might provide a novel treatment strategy for refractory and relapsed T-ALL patients.