Targeting the PI3K/Akt/mTOR signaling pathway as a new therapeutic strategy for personalized treatments in acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the uncontrolled proliferation of lymphoblasts that accumulate in the blood, bone marrow and other organs. It represents 20% of adult acute leukemia and is the most common leukemia in children. The signal transduction pathway mediated by phosphatidylinositol 3-kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) plays a key role in the regulation of important events for cells such as proliferation, differentiation and apoptosis, but also for the development of cancer and resistance to chemotherapy. In fact, the genes involved in the PI3K/Akt/mTOR pathway are often mutated and the activation signal mediated by these proteins is frequently altered in many cancer types, including ALL. Therefore, the components of this pathway are potential new targets for the development of innovative targeted therapies which use molecules that inhibit the key components of those signal transduction pathways with high specificity, and which have a central role in the oncogenesis process. The aim of this study is to evaluate the effects of small-molecule inhibitors (SMIs) on the PI3K/Akt/mTOR pathway using a panel of human leukemic cell lines and primary patient samples. Drugs directed against the Akt and mTOR proteins were used, administered either alone or in combination, to assess their synergistic effects on cells. In particular, MK-2206, GSK690693 and Perifosine are specific inhibitors of Akt, while RAD001 and CCI-779 are directed against mTORC1 and Torin-2 is directed against mTORC1/2. MK-2206, RAD001 and Torin-2 showed a specific cytotoxicity, inducing apoptosis and also caused cell cycle arrest in G0/G1 phase and autophagy both in cell lines and patient samples. They also down-regulated Akt and mTOR, as well as their downstream substrates. Moreover, potential synergies between drugs that hit at different levels of the PI3K/Akt/mTOR signal transduction pathway have been studied: a dual action on two targets, has been analyzed, using either MK-2206 or GSK690693 and RAD001 or CCI-779, that showed a synergistic effect, not observable with Torin-2. Also the efficacy of a triple hit on the same target, i.e. Akt, has been analyzed using MK-2206, GSK690693 and Perifosine: the three drugs displayed a synergistic effect that allowed to minimize drug concentrations. These results emphasize the increasing interest in studying pharmacological and personalized strategies for the development of new potential therapeutic protocols for cancer patients’ treatment, in order to overcome resistances and to improve clinical outcome.