Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia.

Détails

ID Serval
serval:BIB_FBE7D6D662B1
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Ex vivo drug response profiling detects recurrent sensitivity patterns in drug-resistant acute lymphoblastic leukemia.
Périodique
Blood
Auteur(s)
Frismantas V., Dobay M.P., Rinaldi A., Tchinda J., Dunn S.H., Kunz J., Richter-Pechanska P., Marovca B., Pail O., Jenni S., Diaz-Flores E., Chang B.H., Brown T.J., Collins R.H., Uhrig S., Balasubramanian G.P., Bandapalli O.R., Higi S., Eugster S., Voegeli P., Delorenzi M., Cario G., Loh M.L., Schrappe M., Stanulla M., Kulozik A.E., Muckenthaler M.U., Saha V., Irving J.A., Meisel R., Radimerski T., Von Stackelberg A., Eckert C., Tyner J.W., Horvath P., Bornhauser B.C., Bourquin J.P.
ISSN
1528-0020 (Electronic)
ISSN-L
0006-4971
Statut éditorial
Publié
Date de publication
16/03/2017
Peer-reviewed
Oui
Volume
129
Numéro
11
Pages
e26-e37
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Drug sensitivity and resistance testing on diagnostic leukemia samples should provide important functional information to guide actionable target and biomarker discovery. We provide proof of concept data by profiling 60 drugs on 68 acute lymphoblastic leukemia (ALL) samples mostly from resistant disease in cocultures of bone marrow stromal cells. Patient-derived xenografts retained the original pattern of mutations found in the matched patient material. Stromal coculture did not prevent leukemia cell cycle activity, but a specific sensitivity profile to cell cycle-related drugs identified samples with higher cell proliferation both in vitro and in vivo as leukemia xenografts. In patients with refractory relapses, individual patterns of marked drug resistance and exceptional responses to new agents of immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active below 10 nM in B-cell precursor ALL (BCP-ALL) subsets, including MLL-AF4 and TCF3-HLF ALL, and in some T-cell ALLs (T-ALLs), predicting in vivo activity as a single agent and in combination with dexamethasone and vincristine. Unexpected sensitivity to dasatinib with half maximal inhibitory concentration values below 20 nM was detected in 2 independent T-ALL cohorts, which correlated with similar cytotoxic activity of the SRC inhibitor KX2-391 and inhibition of SRC phosphorylation. A patient with refractory T-ALL was treated with dasatinib on the basis of drug profiling information and achieved a 5-month remission. Thus, drug profiling captures disease-relevant features and unexpected sensitivity to relevant drugs, which warrants further exploration of this functional assay in the context of clinical trials to develop drug repurposing strategies for patients with urgent medical needs.
Mots-clé
Antineoplastic Agents/pharmacology, Antineoplastic Combined Chemotherapy Protocols/pharmacology, Cells, Cultured, Coculture Techniques, Drug Resistance, Neoplasm, Heterografts, Humans, Mesenchymal Stromal Cells/pathology, Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy, Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
Pubmed
Web of science
Création de la notice
07/02/2017 18:43
Dernière modification de la notice
04/05/2021 5:37
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