Glucocorticoid resistance is reverted by LCK inhibition in pediatric T-cell acute lymphoblastic leukemia.

Blood
Valentina SerafinBenedetta Accordi

Abstract

Pediatric T-acute lymphoblastic leukemia (T-ALL) patients often display resistance to glucocorticoid (GC) treatment. These patients, classified as prednisone poor responders (PPR), have poorer outcome than do the other pediatric T-ALL patients receiving a high-risk adapted therapy. Because glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to improving the outcome for these patients. Mechanisms underlying resistance are not yet fully unraveled; thus our research focused on the identification of deregulated signaling pathways to point out new targeted approaches. We first identified, by reverse-phase protein arrays, the lymphocyte cell-specific protein-tyrosine kinase (LCK) as aberrantly activated in PPR patients. We showed that LCK inhibitors, such as dasatinib, bosutinib, nintedanib, and WH-4-023, are able to induce cell death in GC-resistant T-ALL cells, and remarkably, cotreatment with dexamethasone is able to reverse GC resistance, even at therapeutic drug concentrations. This was confirmed by specific LCK gene silencing and ex vivo combined treatment of cells from PPR patient-derived xenografts. Moreover, we observed that LCK hyperact...Continue Reading

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Citations

Sep 27, 2018·Carcinogenesis·Marinella N GhezzoNuno R Dos Santos
Jan 16, 2019·Journal of Leukocyte Biology·Liliana Torres-LópezOxana Dobrovinskaya
Jun 13, 2019·Journal of Hematology & Oncology·Hao WangXingxing Zang
Dec 11, 2019·International Journal of Molecular Sciences·Valentina SerafinBenedetta Accordi
Jun 29, 2018·International Journal of Molecular Sciences·Camilla EvangelistiAlberto M Martelli
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Sep 21, 2020·Biochimica Et Biophysica Acta. Reviews on Cancer·Dorien ClarisseKarolien De Bosscher
Jun 4, 2021·Cancer Medicine·Marcela B MansurFrederik W van Delft
Aug 28, 2021·Genes·Valentina BardelliRoberta La Starza

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