TY  - JOUR
AU  - Andersson, E. I.
AU  - Pützer, S.
AU  - Yadav, B.
AU  - Dufva, O.
AU  - Khan, S.
AU  - He, L.
AU  - Sellner, Leopold
AU  - Schrader, A.
AU  - Crispatzu, G.
AU  - Oleś, M.
AU  - Zhang, H.
AU  - Adnan-Awad, S.
AU  - Lagström, S.
AU  - Bellanger, D.
AU  - Mpindi, J. P.
AU  - Eldfors, S.
AU  - Pemovska, T.
AU  - Pietarinen, P.
AU  - Lauhio, A.
AU  - Tomska, K.
AU  - Cuesta-Mateos, C.
AU  - Faber, E.
AU  - Koschmieder, S.
AU  - Brümmendorf, T. H.
AU  - Kytölä, S.
AU  - Savolainen, E-R
AU  - Siitonen, T.
AU  - Ellonen, P.
AU  - Kallioniemi, O.
AU  - Wennerberg, K.
AU  - Ding, W.
AU  - Stern, M-H
AU  - Huber, W.
AU  - Anders, S.
AU  - Tang, J.
AU  - Aittokallio, T.
AU  - Zenz, T.
AU  - Herling, M.
AU  - Mustjoki, S.
TI  - Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.
JO  - Leukemia
VL  - 32
IS  - 3
SN  - 1476-5551
CY  - London
PB  - Springer Nature
M1  - DKFZ-2019-00459
SP  - 774 - 787
PY  - 2018
AB  - 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
KW  - Antineoplastic Agents (NLM Chemicals)
KW  - Biomarkers, Tumor (NLM Chemicals)
KW  - N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide (NLM Chemicals)
KW  - Oxazoles (NLM Chemicals)
KW  - Protein Kinase Inhibitors (NLM Chemicals)
KW  - STAT Transcription Factors (NLM Chemicals)
KW  - Thiazoles (NLM Chemicals)
KW  - Janus Kinases (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:28804127
DO  - DOI:10.1038/leu.2017.252
UR  - https://inrepo02.dkfz.de/record/142742
ER  -