title: Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitors.
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.
authors.affiliation: Experimental Therapeutics Centre, Agency for Science Technology and Research, Singapore.
authors.forename: Meng Ling
authors.initials: ML
authors.lastname: Choong
authors.forename: Christian
authors.initials: C
authors.lastname: Pecquet
authors.forename: Vishal
authors.initials: V
authors.lastname: Pendharkar
authors.forename: Carmen C
authors.initials: CC
authors.lastname: Diaconu
authors.forename: Jacklyn Wei Yan
authors.initials: JW
authors.lastname: Yong
authors.forename: Shi Jing
authors.initials: SJ
authors.lastname: Tai
authors.forename: Si Fang
authors.initials: SF
authors.lastname: Wang
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Defour
authors.forename: Kanda
authors.initials: K
authors.lastname: Sangthongpitag
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Villeval
authors.forename: William
authors.initials: W
authors.lastname: Vainchenker
authors.forename: Stefan N
authors.initials: SN
authors.lastname: Constantinescu
authors.forename: May Ann
authors.initials: MA
authors.lastname: Lee
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D055879:Gene Knock-In Techniques; D019337:Hematologic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000201:enzymology; D009368:Neoplasm Transplantation; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines; D011759:Pyrrolidines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000008:administration & dosage; D014227:Triazines / Q000008:administration & dosage; D014407:Tumor Cells, Cultured; D000096926:Benzenesulfonamides
chemical_list: D053614:Janus Kinase 2; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D011759:Pyrrolidines; D013449:Sulfonamides; D014227:Triazines; C510150:ZSTK474; C528327:fedratinib; D000096926:Benzenesulfonamides; C540383:ruxolitinib; C507926:Jak2 protein, mouse
keywords: JAK2; PI3K; combination treatment; kinases; myeloproliferative neoplasms