PI3K/AKT/mTOR pathway in multiple myeloma: from basic biology to clinical promise

Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is the second most common hematological malignancy. The disease is characterized by the accumulation of abnormal plasma cells in the bone marrow that remains in close association with other cells in the marrow microenvironment. In addition to the genomic alterations that commonly occur in MM, the interaction with cells in the marrow microenvironment promotes signaling events within the myeloma cells that enhances survival of MM cells. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) is such a pathway that is aberrantly activated in a large proportion of MM patients through numerous mechanisms and can play a role in resistance to several existing therapies making this a central pathway in MM pathophysiology. Here, we review the pathway, its role in MM, promising preclinical results obtained thus far and the clinical promise that drugs targeting this pathway have in MM.