Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling

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

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)774-787
Number of pages14
JournalLeukemia
Volume32
Issue number3
DOIs
StatePublished - Mar 1 2018

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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    Andersson, E. I., Pützer, S., Yadav, B., Dufva, O., Khan, S., He, L., Sellner, L., Schrader, A., Crispatzu, G., Oles, M., Zhang, H., Adnan-Awad, S., Lagström, S., Bellanger, D., Mpindi, J. P., Eldfors, S., Pemovska, T., Pietarinen, P., Lauhio, A., ... Mustjoki, S. (2018). Discovery of novel drug sensitivities in T-PLL by high-throughput ex vivo drug testing and mutation profiling. Leukemia, 32(3), 774-787. https://doi.org/10.1038/leu.2017.252