Combination treatment for myeloproliferative neoplasms using JAK and pan‐class I PI 3K inhibitors

Current JAK 2 inhibitors used for myeloproliferative neoplasms ( MPN ) treatment are not specific enough to selectively suppress aberrant JAK 2 signalling and preserve physiological JAK 2 signalling. We tested whether combining a JAK 2 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 JAK 2 (V617F) or thrombopoietin receptor (W515L). Out of 15 kinase inhibitors, the ZSTK474 phosphatydylinositol‐3′‐kinase ( PI 3K) inhibitor molecule showed strong synergic inhibition by C hou and T alalay analysis with JAK2 and JAK2/JAK1 inhibitors. Other pan‐class I, but not gamma or delta specific PI 3K inhibitors, also synergized with JAK 2 inhibitors. Synergy was not observed in Bcr‐Abl transformed cells. The best JAK 2/ JAK 1 and PI 3K inhibitor combination pair (ruxolitinib and GDC0941) reduces spleen weight in nude mice inoculated with Ba/F3 cells expressing TpoR and JAK 2 V617F. It also exerted strong inhibitory effects on erythropoietin‐independent erythroid colonies from MPN patients and JAK 2 V617F knock‐in mice, where at certain doses, a preferential inhibition of JAK 2 V617F mutated progenitors was detected. Our data support the use of a combination of JAK 2 and pan‐class I PI 3K inhibitors in the treatment of MPN s.