Open AccessCo‐targeting the PI3K/ mTOR and JAK2 signalling pathways produces synergistic activity against myeloproliferative neoplasms
Author(s) -
Bartalucci Niccolò,
Tozzi Lorenzo,
Bogani Costanza,
Martinelli Serena,
Rotunno Giada,
Villeval JeanLuc,
Vannucchi Alessandro M.
Publication year - 2013
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12162
Subject(s) - pi3k/akt/mtor pathway , ruxolitinib , haematopoiesis , cancer research , spleen , biology , apoptosis , progenitor cell , pharmacology , signal transduction , microbiology and biotechnology , immunology , stem cell , myelofibrosis , bone marrow , biochemistry
Aberrant JAK 2 signalling plays a central role in myeloproliferative neoplasms ( MPN ). JAK 2 inhibitors have proven to be clinically efficacious, however, they are not mutation‐specific and competent enough to suppress neoplastic clonal haematopoiesis. We hypothesized that, by simultaneously targeting multiple activated signalling pathways, MPN could be more effectively treated. To this end we investigated the efficacy of BEZ 235, a dual PI3K/ mTOR inhibitor, alone and in combination with the JAK 1/ JAK 2 inhibitor ruxolitinib, in different preclinical models of MPN . Single‐agent BEZ 235 inhibited the proliferation and induced cell cycle arrest and apoptosis of mouse and human JAK2 V617F mutated cell lines at concentrations significantly lower than those required to inhibit the wild‐type counterpart, and preferentially prevented colony formation from JAK 2V617F knock‐in mice and patients' progenitor cells compared with normal ones. Co‐treatment of BEZ 235 and ruxolitinib produced significant synergism in all these in‐vitro models. Co‐treatment was also more effective than single drugs in reducing the extent of disease and prolonging survival of immunodeficient mice injected with JAK2 V617F‐mutated Ba/F3‐ EPOR cells and in reducing spleen size, decreasing reticulocyte count and improving spleen histopathology in conditional JAK 2V617F knock‐in mice. In conclusion, combined inhibition of PI3K/ mTOR and JAK 2 signalling may represent a novel therapeutic strategy in MPN .