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