Ex vivo drug response profiling detects recurrent sensitivity patterns in drug resistant ALL
Authors: Frismantas V, Dobay MP, Rinaldi A, Tchinda J, Dunn SH, Kunz J, Richter-Pechanska P, Marovca B, Pail O, Jenni S, Diaz-Flores E, Chang BH, Brown TJ, Collins RH, Uhrig S, Balasubramanian GP, Bandapalli OR, Higi S, Eugster S, Voegeli P, Delorenzi M, Cario G, Loh ML, Schrappe M, Stanulla M, Kulozik AE, Muckenthaler MU, Saha V, Irving JA, Meisel R, Radimerski T, von Stackelberg A, Eckert C, Tyner JW, Horvath P, Bornhauser BC, Bourquin JP
CellNetworks People: Muckenthaler Martina
Journal: Blood. 2017 Jan 25. pii: blood-2016-09-738070. doi: 10.1182/blood-2016-09-738070

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. Patient-derived 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 T-ALLs, 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 T-ALL was treated with dasatinib based on drug profiling information and achieved a five-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 in order to develop drug repurposing strategies for patients with urgent medical needs.