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

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.

SUBMITTER: Nairismagi M-

PROVIDER: S-EPMC5940653 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Nairismägi M -L M- Gerritsen M E ME Li Z M ZM Wijaya G C GC Chia B K H BKH Laurensia Y Y Lim J Q JQ Yeoh K W KW Yao X S XS Pang W L WL Bisconte A A Hill R J RJ Bradshaw J M JM Huang D D Song T L L TLL Ng C C Y CCY Rajasegaran V V Tang T T Tang Q Q QQ Xia X J XJ Kang T B TB Teh B T BT Lim S T ST Ong C K CK Tan J J

Leukemia 20180202 5

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, ...[more]

PMID: 29434279

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Project description:Extranodal natural killer/T-cell lymphoma, nasal type (ENKL), is a rare malignancy of Non-Hodgkin lymphoma characterized by an aggressive clinical course and poor prognosis. It shows strong association with Epstein-Barr virus infection and occurs more commonly in Asia and Latin America. Various genetic alterations have been identified in ENKL by gene expression profiling and sequencing techniques. The frequent deletion of chromosome 6q21 was reported to lead to the silence of several tumor suppressor genes. Also, there have been novel genetic mutations that were recently uncovered and were found to frequently activate several oncogenic pathways, including the JAK/STAT, NF-κB, and MAPK pathways. Besides, we believe that deregulated single genes and epigenetic dysregulation might be relevant to the mechanism of this disease and thus, may have the potential to shed lights on the development of new therapeutic strategies. The consensus on the standard treatment for ENKL has not yet been currently established. For localized ENKL patients, radiotherapy with concurrent chemotherapy and sequential patterns of chemotherapy and radiotherapy are recommended as first-line therapy. As for advanced or relapsed/refractory ENKL patients, the application of non-anthracycline-containing regimens have significantly improved the clinical outcome, contributing to higher response rate, longer overall survival and progression-free survival. Hematopoietic stem cell transplantation is widely recommended for consolidation after a complete remission or partial remission has been achieved. The anti-programmed death 1 antibody, an immune checkpoint inhibitor, has demonstrated favorable results in treating relapsed or refractory ENKL. Of the current ENKL treatment, researchers are still striving to validate how radiotherapy and chemotherapy should be optimally combined and which of the non-anthracycline-containing regimens is superior. In this review, we summarize the main genetic alterations frequently found in ENKL and their role in providing new insights into the therapeutic targets of this disease, and highlight the recent findings regarding new biologic markers, novel therapeutic strategies applied to this intriguing neoplasm.

Dataset Information

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

Publications

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

Similar Datasets

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