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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
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 act...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940653/ https://www.ncbi.nlm.nih.gov/pubmed/29434279 http://dx.doi.org/10.1038/s41375-017-0004-x |
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author | Nairismägi, M. -L. Gerritsen, M. E. Li, Z. M. Wijaya, G. C. Chia, B. K. H. Laurensia, Y. Lim, J. Q. Yeoh, K. W. Yao, X. S. Pang, W. L. Bisconte, A. Hill, R. J. Bradshaw, J. M. Huang, D. Song, T. L. L. Ng, C. C. Y. Rajasegaran, V. Tang, T. Tang, Q. Q. Xia, X. J. Kang, T. B. Teh, B. T. Lim, S. T. Ong, C. K. Tan, J. |
author_facet | Nairismägi, M. -L. Gerritsen, M. E. Li, Z. M. Wijaya, G. C. Chia, B. K. H. Laurensia, Y. Lim, J. Q. Yeoh, K. W. Yao, X. S. Pang, W. L. Bisconte, A. Hill, R. J. Bradshaw, J. M. Huang, D. Song, T. L. L. Ng, C. C. Y. Rajasegaran, V. Tang, T. Tang, Q. Q. Xia, X. J. Kang, T. B. Teh, B. T. Lim, S. T. Ong, C. K. Tan, J. |
author_sort | Nairismägi, M. -L. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-5940653 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-59406532018-05-10 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. Gerritsen, M. E. Li, Z. M. Wijaya, G. C. Chia, B. K. H. Laurensia, Y. Lim, J. Q. Yeoh, K. W. Yao, X. S. Pang, W. L. Bisconte, A. Hill, R. J. Bradshaw, J. M. Huang, D. Song, T. L. L. Ng, C. C. Y. Rajasegaran, V. Tang, T. Tang, Q. Q. Xia, X. J. Kang, T. B. Teh, B. T. Lim, S. T. Ong, C. K. Tan, J. Leukemia Article 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. Nature Publishing Group UK 2018-02-02 2018 /pmc/articles/PMC5940653/ /pubmed/29434279 http://dx.doi.org/10.1038/s41375-017-0004-x Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/. |
spellingShingle | Article Nairismägi, M. -L. Gerritsen, M. E. Li, Z. M. Wijaya, G. C. Chia, B. K. H. Laurensia, Y. Lim, J. Q. Yeoh, K. W. Yao, X. S. Pang, W. L. Bisconte, A. Hill, R. J. Bradshaw, J. M. Huang, D. Song, T. L. L. Ng, C. C. Y. Rajasegaran, V. Tang, T. Tang, Q. Q. Xia, X. J. Kang, T. B. Teh, B. T. Lim, S. T. Ong, C. K. Tan, J. Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma |
title | Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma |
title_full | Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma |
title_fullStr | Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma |
title_full_unstemmed | Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma |
title_short | Oncogenic activation of JAK3-STAT signaling confers clinical sensitivity to PRN371, a novel selective and potent JAK3 inhibitor, in natural killer/T-cell lymphoma |
title_sort | oncogenic activation of jak3-stat signaling confers clinical sensitivity to prn371, a novel selective and potent jak3 inhibitor, in natural killer/t-cell lymphoma |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5940653/ https://www.ncbi.nlm.nih.gov/pubmed/29434279 http://dx.doi.org/10.1038/s41375-017-0004-x |
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