Constitutive JAK2 signaling is central to myeloproliferative neoplasm (MPN) pathogenesis and results in activation of STAT, PI3K/AKT, and MEK/ERK signaling.
Herein, we will review the clinically relevant inhibitors of the PI3K pathway that have been evaluated or hold promise for the treatment of Ph-ve MPNs.
Molecular profiling of CD34+ cells and granulocytes of MPN determined gene expression patterns beyond their recognized function in disease pathogenesis that included dominant up-regulation of PI3K/AKT signaling.
In this review, we present some clinical and experimental evidence showing that the PI3K/Akt/mTOR pathway could represent a therapeutic target in MPNs.
Genetic disruption of SHP2 or treatment of oncogene-bearing cells with a novel SHP2 inhibitor alone or in combination with the PI3K inhibitor corrects MPD by disrupting a protein complex involving p85α, SHP2, and Gab2.
Many drugs are now under investigations targeting different pathways critical for MPN development, such as the JAK-STAT (JAK2 inhibitors: INCB018424 or ruxolitinib, TG101348 or SAR302503, CYT387, SB1518, CEP701 and LY2784544) and the PI3K/AKT/mTOR (everolimus) pathways, or act through remodeling of chromatin with a key role in epigenetics (givinostat, panobinostat and vorinostat).