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

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.

• Authors: E I Andersson, S Pützer, B Yadav, O Dufva, S Khan, L He, L Sellner, A Schrader, G Crispatzu, M Oleś, H Zhang, S Adnan-Awad, S Lagström, D Bellanger, J P Mpindi, S Eldfors, T Pemovska, P Pietarinen, A Lauhio, K Tomska, C Cuesta-Mateos, E Faber, S Koschmieder, T H Brümmendorf, S Kytölä, E-R Savolainen, T Siitonen, P Ellonen, O Kallioniemi, K Wennerberg, W Ding, M-H Stern, W Huber, S Anders, J Tang, T Aittokallio, T Zenz, M Herling, S Mustjoki
• Journal: Leukemia (Leukemia) Vol. 32 Issue 3 Pg. 774-787 (03 2018) ISSN: 1476-5551 [Electronic] England
• PMID: 28804127 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Aged
• Aged, 80 and over
• Antineoplastic Agents (pharmacology, therapeutic use)
• Biomarkers, Tumor
• Cell Cycle (genetics)
• Cell Line, Tumor
• Chromosome Aberrations
• Drug Resistance, Neoplasm
• Drug Screening Assays, Antitumor
• Female
• Gene Expression
• Gene Expression Profiling
• High-Throughput Screening Assays
• Humans
• Janus Kinases (metabolism)
• Leukemia, Prolymphocytic, T-Cell (drug therapy, genetics, metabolism)
• Male
• Middle Aged
• Molecular Targeted Therapy
• Mutation
• Oxazoles (pharmacology)
• Phenotype
• Protein Kinase Inhibitors (pharmacology)
• STAT Transcription Factors (metabolism)
• Thiazoles (pharmacology)