%0 Journal Article
%A Andersson, E. I.
%A Pützer, S.
%A Yadav, B.
%A Dufva, O.
%A Khan, S.
%A He, L.
%A Sellner, Leopold
%A Schrader, A.
%A Crispatzu, G.
%A Oleś, M.
%A Zhang, H.
%A Adnan-Awad, S.
%A Lagström, S.
%A Bellanger, D.
%A Mpindi, J. P.
%A Eldfors, S.
%A Pemovska, T.
%A Pietarinen, P.
%A Lauhio, A.
%A Tomska, K.
%A Cuesta-Mateos, C.
%A Faber, E.
%A Koschmieder, S.
%A Brümmendorf, T. H.
%A Kytölä, S.
%A Savolainen, E-R
%A Siitonen, T.
%A Ellonen, P.
%A Kallioniemi, O.
%A Wennerberg, K.
%A Ding, W.
%A Stern, M-H
%A Huber, W.
%A Anders, S.
%A Tang, J.
%A Aittokallio, T.
%A Zenz, T.
%A Herling, M.
%A Mustjoki, S.
%T Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.
%J Leukemia
%V 32
%N 3
%@ 1476-5551
%C London
%I Springer Nature
%M DKFZ-2019-00459
%P 774 - 787
%D 2018
%X T-cell prolymphocytic leukemia (T-PLL) is a rare and aggressive neoplasm of mature T-cells with an urgent need for rationally designed therapies to address its notoriously chemo-refractory behavior. The median survival of T-PLL patients is <2 years and clinical trials are difficult to execute. Here we systematically explored the diversity of drug responses in T-PLL patient samples using an ex vivo drug sensitivity and resistance testing platform and correlated the findings with somatic mutations and gene expression profiles. Intriguingly, all T-PLL samples were sensitive to the cyclin-dependent kinase inhibitor SNS-032, which overcame stromal-cell-mediated protection and elicited robust p53-activation and apoptosis. Across all patients, the most effective classes of compounds were histone deacetylase, phosphoinositide-3 kinase/AKT/mammalian target of rapamycin, heat-shock protein 90 and BH3-family protein inhibitors as well as p53 activators, indicating previously unexplored, novel targeted approaches for treating T-PLL. Although Janus-activated kinase-signal transducer and activator of transcription factor (JAK-STAT) pathway mutations were common in T-PLL (71
%K Antineoplastic Agents (NLM Chemicals)
%K Biomarkers, Tumor (NLM Chemicals)
%K N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide (NLM Chemicals)
%K Oxazoles (NLM Chemicals)
%K Protein Kinase Inhibitors (NLM Chemicals)
%K STAT Transcription Factors (NLM Chemicals)
%K Thiazoles (NLM Chemicals)
%K Janus Kinases (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:28804127
%R 10.1038/leu.2017.252
%U https://inrepo02.dkfz.de/record/142742