Journal Article

DKFZ-2019-00459

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling.

Andersson, E. I. ; Pützer, S. ; Yadav, B. ; Dufva, O. ; Khan, S. ; He, L. ; Sellner, L.DKFZ* ; Schrader, A. ; Crispatzu, G. ; Oleś, M. ; Zhang, H. ; Adnan-Awad, S. ; Lagström, S. ; Bellanger, D. ; Mpindi, J. P. ; Eldfors, S. ; Pemovska, T. ; Pietarinen, P. ; Lauhio, A. ; Tomska, K.DKFZ* ; Cuesta-Mateos, C. ; Faber, E. ; Koschmieder, S. ; Brümmendorf, T. H. ; Kytölä, S. ; Savolainen, E.-R. ; Siitonen, T. ; Ellonen, P. ; Kallioniemi, O. ; Wennerberg, K. ; Ding, W. ; Stern, M.-H. ; Huber, W. ; Anders, S. ; Tang, J. ; Aittokallio, T. ; Zenz, T.DKFZ* ; Herling, M. ; Mustjoki, S.

2018
Springer Nature London

This record in other databases:  

Please use a persistent id in citations: doi:10.1038/leu.2017.252

Abstract: 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% of patients), JAK-STAT inhibitor responses were not directly linked to those or other T-PLL-specific lesions. Overall, we found that genetic markers do not readily translate into novel effective therapeutic vulnerabilities. In conclusion, novel classes of compounds with high efficacy in T-PLL were discovered with the comprehensive ex vivo drug screening platform warranting further studies of synergisms and clinical testing.

Keyword(s): Antineoplastic Agents ; Biomarkers, Tumor ; N-(5-(((5-(1,1-dimethylethyl)-2-oxazolyl)methyl)thio)-2-thiazolyl)-4-piperidinecarboxamide ; Oxazoles ; Protein Kinase Inhibitors ; STAT Transcription Factors ; Thiazoles ; Janus Kinases

---

Contributing Institute(s):

1. Translationale Onkologie (G100)
2. Molekulare Therapie in der Hämatologie und Onkologie (G250)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2018

---

Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 10 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

---