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Inhibition of related JAK / STAT pathways with molecular targeted drugs shows strong synergy with ruxolitinib in chronic myeloproliferative neoplasm
Author(s) -
Barrio Santiago,
Gallardo Miguel,
Arenas Alicia,
Ayala Rosa,
Rapado Inmaculada,
Rueda Daniel,
JiménezUbieto Ana,
Albizua Enriqueta,
Burgaleta Carmen,
Gilsanz Florinda,
MartinezLopez Joaquin
Publication year - 2013
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12308
Subject(s) - ruxolitinib , sorafenib , dasatinib , cancer research , myeloproliferative neoplasm , mapk/erk pathway , myelofibrosis , medicine , pharmacology , stat , bone marrow , immunology , chemistry , signal transduction , stat3 , imatinib , biochemistry , myeloid leukemia , hepatocellular carcinoma
Summary This study aimed to assess the antitumour effects, molecular mechanisms of action, and potential synergy of ruxolitinib with sorafenib, KNK 437, dasatinib, and perifosine, in Philadelphia‐negative chronic myeloproliferative neoplasms ( MPN ). Cytotoxic and cytostatic effects of the different compounds were determined in the JAK 2 V 617 F ‐positive cell lines, HEL and B a/ F 3 JAK2V617F EPOR , and in primary mononuclear and bone marrow CD 34‐positive cells from 19 MPN patients. Ruxolitinib [50% inhibitory concentration ( IC 50 ) PV = 15 nmol/l], as well as sorafenib (IC 50PV = 8 μ mol / l ), KNK 437 (IC 50PV = 100 μ mol / l ), and perifosine (IC 50PV = 15 μ mol / l ), were able to inhibit proliferation in cell line models and in primary cells from MPN patients. Dasatinib, KNK 437, and sorafenib showed a strong synergistic effect in combination with ruxolitinib [combination index ( CI ) PV < 0·3]. Western blot confirmed that ruxolitinib blocked ERK , and consequently STAT 5 activation, sorafenib inhibited ERK , P 38 and STAT 5, dasatinib blocked SRC and STAT 5, and KNK 437 decreased the stability of the JAK 2 protein, reducing its expression. Inhibiting JAK 2‐related proliferative pathways has the potential to inhibit cell proliferation in MPN s. Furthermore, the combination of ruxolitinib with inhibitors that target these pathways has a strong synergistic effect, which may be due to decreased activation of the common effector, STAT 5.