AKT is a therapeutic target in myeloproliferative neoplasms

Abstract

The majority of patients with BCR-ABL1-negative myeloproliferative neoplasms (MPN) harbor mutations in JAK2 or MPL, which lead to constitutive activation of the JAK/STAT, PI3K, and ERK signaling pathways. JAK inhibitors by themselves are inadequate in producing selective clonal suppression in MPN and are associated with hematopoietic toxicities. MK-2206 is a potent allosteric AKT inhibitor that was well tolerated, including no evidence of myelosuppression, in a phase I study of solid tumors. Herein, we show that inhibition of PI3K/AKT signaling by MK-2206 affected the growth of both JAK2V617F or MPLW515L-expressing cells via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. Moreover, we demonstrate that MK-2206 synergizes with Ruxolitinib in suppressing the growth of JAK2V617F mutant SET2 cells. Importantly MK-2206 suppressed colony formation from hematopoietic progenitor cells in patients with primary myelofibrosis (PMF) and alleviated hepatosplenomegaly and reduced megakaryocyte burden in the bone marrows, livers and spleens of mice with MPLW515L-induced MPN. Together, these findings establish AKT as a rational therapeutic target in the MPNs.

Current pre-clinical and clinical advances in the BCR-ABL1-positive and -negative chronic myeloproliferative neoplasms

“…Combining JAK inhibitors with other targeted drugs, including immunomodulators, epigenetic agents and telomerase inhibitors, are now being pursued, in tandem with efforts to unravel the underlying molecular complexities. 38 …”

Co-operating STAT5 and AKT signaling pathways in chronic myeloid leukemia and mastocytosis: possible new targets of therapy

“…73 In the same study, MK-2206 alleviated hepato-splenomegaly and reduced the megakaryocyte burden in the BM, liver and spleen of mice with MPL W515L-induced MPN. 73 However, most of these effects were only observed at concentrations of MK-2206 above 1.0 μM.…”

“…72 It has also been shown that inhibition of PI3K/AKT signaling by MK-2206 affects the growth of both JAK2 V617F-or MPLW515L-expressing primary neoplastic cells and cell lines via reduced phosphorylation of AKT and inhibition of its downstream signaling molecules. 73 In the same study, MK-2206 alleviated hepato-splenomegaly and reduced the megakaryocyte burden in the BM, liver and spleen of mice with MPL W515L-induced MPN. 73 However, most of these effects were only observed at concentrations of MK-2206 above 1.0 μM.…”

“…73 However, most of these effects were only observed at concentrations of MK-2206 above 1.0 μM. 73 All in all, the currently available AKT inhibitors exhibit IC50 values at the micromolar range, suggesting that there is a need to develop inhibitors of AKT acting at the nanomolar range. In addition, the use of AKT inhibitors in combination may increase their effects on cell proliferation.…”

Tetraspanin CD9 participates in dysmegakaryopoiesis and stromal interactions in primary myelofibrosis

“…44 In the same way, the role of the Akt pathway driven by CD9 in PMF megakaryocytes is consistent with the findings of a recent study that established Akt as a rational therapeutic target for the treatment of patients with myeloproliferative neoplasms. 45 In brief, our results indicate original therapeutic avenues targeting hematopoietic cell-stroma interactions in PMF.…”