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

Leukemia. 2018 Mar;32(3):774-787. doi: 10.1038/leu.2017.252. Epub 2017 Aug 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / 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
  • Leukemia, Prolymphocytic, T-Cell / genetics*
  • Leukemia, Prolymphocytic, T-Cell / metabolism
  • Male
  • Middle Aged
  • Molecular Targeted Therapy
  • Mutation*
  • Oxazoles / pharmacology
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • STAT Transcription Factors / metabolism
  • Thiazoles / pharmacology


  • 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