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

Résumé fourni par la source

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.

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