Journal
LEUKEMIA
Volume 32, Issue 5, Pages 1147-1156Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41375-017-0004-x
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Funding
- Singapore Ministry of Health's National Medical Research Council [NMRC/TCR/010-NCC/2013]
- Guangdong Innovative and Entrepreneurial Research Team Program [2016ZT06S638, 2016ZT06S252]
- Sci-Tech Project Foundation of Guangzhou City [201707020039]
- Tanoto Foundation as Professorship in Medical Oncology
- New Century Foundation Limited
- Ling Foundation
- Singapore National Cancer Centre Research Fund
- ONCO ACP Cancer Collaborative Scheme
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Aberrant activation of the JAK3-STAT signaling pathway is a characteristic feature of many hematological malignancies. In particular, hyperactivity of this cascade has been observed in natural killer/T-cell lymphoma (NKTL) cases. Although the first-in-class JAK3 inhibitor tofacitinib blocks JAK3 activity in NKTL both in vitro and in vivo, its clinical utilization in cancer therapy has been limited by the pan-JAK inhibition activity. To improve the therapeutic efficacy of JAK3 inhibition in NKTL, we have developed a highly selective and durable JAK3 inhibitor PRN371 that potently inhibits JAK3 activity over the other JAK family members JAK1, JAK2, and TYK2. PRN371 effectively suppresses NKTL cell proliferation and induces apoptosis through abrogation of the JAK3-STAT signaling. Moreover, the activity of PRN371 has a more durable inhibition on JAK3 compared to tofacitinib in vitro, leading to significant tumor growth inhibition in a NKTL xenograft model harboring JAK3 activating mutation. These findings provide a novel therapeutic approach for the treatment of NKTL.
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