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

Valentina Serafin, Giorgia Capuzzo, Gloria Milani, Sonia Anna Minuzzo, Marica Pinazza, Roberta Bortolozzi, Silvia Bresolin, Elena Porcù, Chiara Frasson, Stefano Indraccolo, Giuseppe Basso and Benedetta Accordi

Key points

  • Resistance to glucocorticoid treatment in pediatric T-ALL can be reverted by LCK inhibitors in vitro and in vivo.

  • IL-4 overexpression contributes to LCK-induced glucocorticoid resistance

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 compared to the other pediatric T-ALL patients receiving a high-risk adapted therapy. Since glucocorticoids are administered to ALL patients during all the different phases of therapy, GC resistance represents an important challenge to be addressed in order to improve 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, co-treatment with Dexamethasone is able to revert 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 hyperactivation in PPR patients upregulates the CALCINEURIN/NFAT signaling triggering to IL-4 overexpression. GC sensitive cells cultured with IL-4 display an increased resistance to Dexamethasone, while the inhibition of IL-4 signaling was able to increase GC-induced apoptosis in resistant cells. Treatment with Dexamethasone and Dasatinib resulted also able to impair engraftment of leukemia cells in vivo. Our results suggest a quickly actionable approach to support conventional therapies and overcome GC resistance in pediatric T-ALL patients.

  • Submitted May 11, 2017.
  • Accepted October 30, 2017.