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DEX and DAS impair in vivo T-ALL propagation
PDX with such an activating genetic lesion (LK287, FIP1L1-PDGFRA). Cytotoxicity to DAS is significantly increased upon combination with DEX. Our data indicate drug synergy between DAS and DEX at clinically relevant concentrations. A previous, mostly in vitro, study advocat- ed the use of DEX+DAS in GC resistant T-ALL.28 Our extended studies indicate DEX+DAS act synergistically in the majority of cell lines and PDX tested independent of their prior sensitivity to DEX. The potential of DEX+DAS to revert GC resistance is an exciting observation. GC resistance is frequently observed in relapsed/refractory T-ALL,4 and DEX+DAS provide a clinically actionable approach to re-sensitize T-ALL resistant to DEX.
The implementation of DAS into clinical management would benefit from the identification of a reliable response biomarker. Although LCK activation status (ratio p-Y416SRC/LCK) strongly correlates with DAS sensitivity in cell lines, we were unable to corroborate this observa- tion in PDX cells. Sample size and intricacies of in vitro assays using PDX cells could provide possible explana- tions for these inconsistencies. Nevertheless, in vivo drug synergy was observed in the majority of samples tested. Of interest, drug response profiling of T-ALL samples sug- gested SRC pathway activation may represent a response biomarker.31
The mechanism underlying the observed drug synergy remains to be fully elucidated. T-cell activation can be blocked by using clinically relevant concentrations of the tyrosine kinase inhibitor DAS, which binds to the ATP- binding pocket of LCK thereby preventing the phosphory- lation of the activating loop of the kinase domain p-Y416SRC.21,32 When DEX is combined with DAS, physio- logical CD3+ T-cell proliferation is reduced in an additive way.33,34 Furthermore, it has been previously suggested that the Calcineurin/NFAT/IL-4 axis is activated in patients exhibiting a prednisone poor response.28 We have shown here that combination of DEX+DAS significantly increases GILZ gene expression, reflecting increased tran- scriptional activity of the GC receptor. We thus hypothe- size that inhibition of LCK disrupts the TCR-GR complex and established crosstalk between the TCR and GR path-
References
1. Marks DI, Paietta EM, Moorman AV, et al. T-cell acute lymphoblastic leukemia in adults: clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993). Blood. 2009;114(25):5136- 5145.
2.Patrick K, Wade R, Goulden N, et al. Outcome for children and young people with early T-cell precursor acute lym- phoblastic leukaemia treated on a contem- porary protocol, UKALL 2003. Br J Haematol. 2014;166(3):421-424.
3. Goldberg JM, Silverman LB, Levy DE, et al. Childhood T-cell acute lymphoblastic leukemia: the Dana-Farber Cancer Institute acute lymphoblastic leukemia consortium experience. J Clin Oncol. 2003;21(19):3616- 3622.
4. Raetz EA, Borowitz MJ, Devidas M, et al. Reinduction platform for children with first marrow relapse of acute lymphoblastic leukemia: a Children's Oncology Group
ways leading to dissociation and transcriptional activation of the GR.13
To conclude, drug resistant T-ALL continues to repre- sent an unmet clinical need. We provide further support for the inclusion of DAS in the treatment of T-ALL. It has been reported that DAS in combination with conventional chemotherapy is safe and well tolerated in children and young adults, although hematologic toxicity was signifi- cant.35 Thus, the DEX+DAS combination should be con- sidered in the early phase setting to evaluate toxicity and efficacy in patients with GC resistant disease with or without cerebral spinal fluid involvement.
Disclosures
No conflicts of interest to disclose.
Contributions
FWvD, AKH and YS designed the research; YS performed the research; YS, MCB, HJB, OH and RT designed and performed the in vivo experiments; FWvD, AKH and YS analyzed the data and wrote the paper; SN and AE performed the bioinformatics analysis; CH performed brain histology and imaging; JV, OH and CH reviewed the manuscript.
Acknowledgments
The authors would like to thank patients, parents, and hospital staff at the Great North Children’s Hospital, Newcastle upon Tyne, UK, for their valuable collaboration. The authors would like to thank Lynn Stevenson and Clare Orange, University of Glasgow, for brain histology and imaging. The brain histology slides were scanned by Glasgow University slide scanning and image analysis service at the Queen Elizabeth University Hospital, Glasgow. CH was funded by the Chief Scientist Office (ETM/374).
Funding
This work was supported by a Newcastle University Research Fellowship (to FWvD), Chinese Scholarship Council (CSC) (to YS), JGW Patterson Foundation (to MCB), North of England
Children’s Cancer FWvD).
J Clin Oncol. 2008;26(24):3971-3978.
5. Inaba H, Pui CH. Glucocorticoid use in acute lymphoblastic leukaemia. Lancet Oncol. 2010;11(11):1096-1106.
6. Pui CH, Carroll WL, Meshinchi S, Arceci RJ. Biology, risk stratification, and therapy of pediatric acute leukemias: an update. J Clin Oncol. 2011;29(5):551-565.
7. Pui CH, Mullighan CG, Evans WE, Relling MV. Pediatric acute lymphoblastic leukemia: where are we going and how do we get there? Blood. 2012;120(6):1165-1174.
8. Dordelmann M, Reiter A, Borkhardt A, et al. Prednisone response is the strongest predic- tor of treatment outcome in infant acute lymphoblastic leukemia. Blood. 1999; 94(4):1209-1217.
9. Hongo T, Yajima S, Sakurai M, Horikoshi Y, Hanada R. In vitro drug sensitivity testing can predict induction failure and early relapse of childhood acute lymphoblastic leukemia. Blood. 1997;89(8):2959-2965.
10. Kaspers GJ, Wijnands JJ, Hartmann R, et al. Immunophenotypic cell lineage and in vitro cellular drug resistance in childhood relapsed
Research, Action Medical Research (to
acute lymphoblastic leukaemia. Eur J
Cancer. 2005;41(9):1300-1303.
11. Klumper E, Pieters R, Veerman AJ, et al. In
vitro cellular drug resistance in children with relapsed/refractory acute lymphoblastic leukemia. Blood. 1995;86(10):3861-3868.
12.Pieters R, den Boer ML, Durian M, et al. Relation between age, immunophenotype and in vitro drug resistance in 395 children with acute lymphoblastic leukemia-implica- tions for treatment of infants. Leukemia. 1998;12(9):1344-1348.
13. Jamieson CA, Yamamoto KR. Crosstalk pathway for inhibition of glucocorticoid- induced apoptosis by T cell receptor signal- ing. Proc Natl Acad Sci U S A. 2000; 97(13):7319-7324.
14.Ashwell JD, King LB, Vacchio MS. Cross- talk between the T cell antigen receptor and the glucocorticoid receptor regulates thymo- cyte development. Stem Cells. 1996;14(5):490-500.
15. Cui Y, Onozawa M, Garber HR, et al. Thymic expression of a T-cell receptor tar- geting a tumor-associated antigen coex- pressed in the thymus induces T-ALL.
study[corrected].
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