Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.

Choong, Meng Ling;Pecquet, Christian;Pendharkar, Vishal;Diaconu, Carmen C;Lee, May Ann;et.al.
(2013) Journal of Cellular and Molecular Medicine (Print) : a journal of translational medicine — Vol. 17, n° 11, p. 1397-1409 (2013)

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Abstract
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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Choong, M. L., Pecquet, C., Pendharkar, V., Diaconu, C. C., Yong, J. W. Y., Tai, S. J., Wang, S. F., Defour, J.-P., Sangthongpitag, K., Villeval, J.-L., Vainchenker, W., Constantinescu, S., & Lee, M. A. (2013). Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors. Journal of Cellular and Molecular Medicine (Print) : a journal of translational medicine, 17(11), 1397-1409. https://doi.org/10.1111/jcmm.12156 (Original work published 2013)