The AKT/mTOR Pathway: A Potential Therapeutic Target in Acute Myeloid Leukemia

Abstract

Acute Myeloid Leukemia (AML) is a complex heterogeneous malignancy of myeloid origin and one of the most common adult leukemias accounting for the highest percent of acute leukemia related deaths. Despite important therapeutic advances, AML still associates with poor prognosis, high relapse rates, and resistance to chemotherapy. Early treatment modalities relied on intensive chemotherapy or investigational drugs for high-risk patients. Currently, therapy against AML encompasses more targeted approaches for specific mutations or disrupted pathways. The PI3K/AKT/mTOR pathway is activated in 60% of AML patients. Everolimus (EV), an mTOR inhibitor, improved the treatment of relapse-refractory AML patients, when combined with other therapeutic agents. In some subtypes of AML, all-trans retinoic acid (ATRA), a hormone playing a major role in differentiation, proved beneficial, alone or combined with other drugs, like arsenic trioxide (ATO). We explored the effect of ATO, ATRA, EV, as single agents or as double or triple combinations on AML. Treated xenograft AML mice with ATO, ATRA, EV, ATO/ ATRA, or ATO/ ATRA /EV, were monitored for survival, or humanely sacrificed at day 28 to assess leukemic burden by immunophenotyping. The effect of single agents, select double, or triple combinations was assessed on cell growth and the AKT/mTOR pathway, in AML cell lines presenting different mutations. We demonstrated that the triple combination ATO/ ATRA /EV significantly prolonged survival of AML xenografted mice and reached cure for some animals. This combination sharply reduced leukemic burden in the bone marrow of xenografted animals. At the cellular and molecular levels, ATO/ ATRA /EV induced growth arrest of different AML cell lines, and inactivated the AKT pathway, through abolishing the downstream mTOR pathway and reducing the expression of p-ERK in AML cells. Collectively, our results demonstrate the importance of targeting the AKT/mTOR pathway in AML and warrant future clinical studies combining mTOR inhibitors with ATRA and ATO as a promising targeted therapy in AML.