2. Academic Validation
  3. Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma

Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma

  • Leukemia. 2018 May;32(5):1147-1156. doi: 10.1038/s41375-017-0004-x.
M -L Nairismägi 1,  M E Gerritsen 2,  Z M Li 3 4,  G C Wijaya 3 4,  B K H Chia 1,  Y Laurensia 1,  J Q Lim 1,  K W Yeoh 5,  X S Yao 3 4,  W L Pang 1,  A Bisconte 2,  R J Hill 2,  J M Bradshaw 2,  D Huang 1,  T L L Song 1,  C C Y Ng 3 4,  V Rajasegaran 3 4,  T Tang 6,  Q Q Tang 3 4,  X J Xia 7,  T B Kang 7,  B T Teh 3 4 8,  S T Lim 1 6 9,  C K Ong 10 11,  J Tan 12 13
Affiliations

Affiliations

  • 1 Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  • 2 Principia Biopharma, South San Francisco, CA, USA.
  • 3 Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
  • 4 Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore, Singapore.
  • 5 Department of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  • 6 Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  • 7 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China.
  • 8 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
  • 9 Office of Education, Duke-NUS Graduate Medical School, Singapore, Singapore.
  • 10 Lymphoma Genomic Translational Research Laboratory, Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore. [email protected].
  • 11 Genome Institute of Singapore, A*STAR, Singapore, Singapore. [email protected].
  • 12 Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore. [email protected].
  • 13 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, China. [email protected].
PMID: 29434279 DOI: 10.1038/s41375-017-0004-x
Abstract

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.

Figures
Products