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Ex vivo drug response profiling detects recurrent sensitivity patterns in drug resistant ALL

Frismantas, Viktoras and Dobay, Maria Pamela and Rinaldi, Anna and Kunz, Joachim and Marovca, Blerim and Horvath, Peter and Higi, Salome and Eugster, Sabrina and Delorenzi, Mauro and Cario, Gunnar and Stanulla, Martin and Kulozik, Andreas E. and Muckenthaler, Martina and Eckert, Cornelia and Radimerski, Thomas and Bornhauser, Beat C. and Bourquin, Jean-Pierre (2017) Ex vivo drug response profiling detects recurrent sensitivity patterns in drug resistant ALL. Blood. ISSN 0006-4971

Abstract

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 co-cultures on bone marrow stromal cells. Patientderived
xenografts retained the original pattern of mutations found in the matched patient
material. Stromal co-culture did not prevent leukemia cell cycle activity, while 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 cases with refractory relapses, individual
patterns of marked drug resistance, but also exceptional responses to new agents of
immediate clinical relevance were detected. The BCL2-inhibitor venetoclax was highly active
below 10 nM in BCP-ALL subsets including MLL-AF4 and TCF3-HLF ALL, and in some TALLs,
predicting in vivo activity as a single agent and in combination with dexamethasone
and vincristine. Unexpected sensitivity to dasatinib with IC50 values below 20 nM was
detected in two 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 TALL
was treated with dasatinib based on drug profiling information and achieved a fivemonth
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 in order to develop drug repurposing strategies for patients with
urgent medical needs.

Item Type: Article
Date Deposited: 27 Jan 2017 00:45
Last Modified: 27 Jan 2017 00:45
URI: https://oak.novartis.com/id/eprint/25521

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