Development and Clinical Applications of PI3K/AKT/mTOR Pathway Inhibitors as a Therapeutic Option for Leukemias.

ABSTRACT

Leukemias are hematological neoplasms characterized by dysregulations in several cellular signaling pathways, prominently including the PI3K/AKT/mTOR pathway. Since this pathway is associated with several important cellular mechanisms, such as proliferation, metabolism, survival, and cell death, its hyperactivation significantly contributes to the development of leukemias. In addition, it is a crucial prognostic factor, often correlated with therapeutic resistance. Changes in the PI3K/AKT/mTOR pathway are identified in more than 50% of cases of acute leukemia, especially in myeloid lineages. Furthermore, these changes are highly frequent in cases of chronic lymphocytic leukemia, especially those with a B cell phenotype, due to the correlation between the hyperactivation of B cell receptors and the abnormal activation of PI3Kδ. Thus, the search for new therapies that inhibit the activity of the PI3K/AKT/mTOR pathway has become the objective of several clinical studies that aim to replace conventional oncological treatments that have high rates of toxicities and low specificity with target-specific therapies offering improved patient quality of life. In this review we describe the PI3K/AKT/mTOR signal transduction pathway and its implications in leukemogenesis. Furthermore, we provide an overview of clinical trials that employed PI3K/AKT/mTOR inhibitors either as monotherapy or in combination with other cytotoxic agents for treating patients with various types of leukemias. The varying degrees of treatment efficacy are also reported.