期刊
JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
卷 17, 期 11, 页码 1397-1409出版社
WILEY
DOI: 10.1111/jcmm.12156
关键词
combination treatment; kinases; myeloproliferative neoplasms; JAK2; PI3K
资金
- F.R.S.-F.N.R.S., Belgium
- Salus Sanguinis Foundation
- Action de Recherche Concertee of the University catholique de Louvain, Brussels
- Fondation contre le Cancer, Brussels
- PAI Program, Belgium
- Atlantic Philanthropies, New York
- Sectorial Operational Program Human Resources Development [POSDRU/89/1.5/S/64109]
- F.R.S.-F.N.R.S./F.R.I.A. fellowships
- Agency for Science Technology and Research (A*STAR), Singapore
- Ludwig Institute for Cancer Research
Current JAK2 inhibitors used for myeloproliferative neoplasms (MPN) treatment are not specific enough to selectively suppress aberrant JAK2 signalling and preserve physiological JAK2 signalling. We tested whether combining a JAK2 inhibitor with a series of serine threonine kinase inhibitors, targeting nine signalling pathways and already used in clinical trials, synergized in inhibiting growth of haematopoietic cells expressing mutant and wild-type forms of JAK2 (V617F) or thrombopoietin receptor (W515L). Out of 15 kinase inhibitors, the ZSTK474 phosphatydylinositol-3-kinase (PI3K) inhibitor molecule showed strong synergic inhibition by Chou and Talalay analysis with JAK2 and JAK2/JAK1 inhibitors. Other pan-class I, but not gamma or delta specific PI3K inhibitors, also synergized with JAK2 inhibitors. Synergy was not observed in Bcr-Abl transformed cells. The best JAK2/JAK1 and PI3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK2 V617F. It also exerted strong inhibitory effects on erythropoietin-independent erythroid colonies from MPN patients and JAK2 V617F knock-in mice, where at certain doses, a preferential inhibition of JAK2 V617F mutated progenitors was detected. Our data support the use of a combination of JAK2 and pan-class I PI3K inhibitors in the treatment of MPNs.
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