RESUMO
The phosphatidylinositol 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) are two major signaling molecules in the PI3K/Akt/mTOR signal transduction cascade. This pathway is a key regulator of a wide range of physiological cell processes which include proliferation, differentiation, survival, metabolism, exocytosis, motility, and autophagy. However, aberrantly upregulated PI3K/Akt/mTOR signaling characterizes many types of cancers where it negatively influences response to therapeutic treatments. Therefore, targeting PI3K/Akt/mTOR signaling with small molecule inhibitors could improve cancer patient outcome. The PI3K/Akt/mTOR signaling network is activated in acute leukemias of both myelogenous and lymphoid lineage, where it correlates with poor prognosis and enhanced drug-resistance. The catalytic sites of PI3K and mTOR share a high degree of sequence homology. This feature has allowed the synthesis of ATP-competitive compounds that targeted the catalytic site of both PI3K and mTOR (e.g. PI-103, NVP-BEZ235). In preclinical settings, dual PI3K/mTOR inhibitors displayed a much stronger cytotoxicity against leukemic cells than either PI3K inhibitors or allosteric mTOR inhibitors, such as rapamycin and its derivatives (rapalogs). At variance with rapamycin/rapalogs, dual PI3K/mTOR inhibitors targeted both mTOR complex 1 and mTOR complex 2, and inhibited the rapamycin-resistant phosphorylation of eukaryotic initiation factor 4E-binding protein 1, resulting in a marked inhibition of oncogenetic protein translation in leukemic cells. Hence, they strongly reduced the proliferation rate and induced an important apoptotic response. Here, we reviewed the evidence documenting that dual PI3K/mTOR inhibitors represent a promising option for future targeted therapies of leukemic patients.
RESUMO
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising from T-cell progenitors. T-ALL accounts for 15% of newly diagnosed ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of polychemotherapy schemes, the outcome of relapsed/chemoresistant T-ALL cases is still poor. A signaling pathway that is frequently upregulated in T-ALL, is the phosphatidylinositol 3-kinase/Akt/mTOR network. To explore whether Akt could represent a target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines and primary cells from T-ALL patients. MK-2206 decreased T-ALL cell line viability by blocking leukemic cells in the G(0)/G(1) phase of the cell cycle and inducing apoptosis. MK-2206 also induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting analysis documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3α/ß and FOXO3A, in response to MK-2206. MK-2206 was cytotoxic to primary T-ALL cells and induced apoptosis in a T-ALL patient cell subset (CD34(+)/CD4(-)/CD7(-)), which is enriched in leukemia-initiating cells. Taken together, our findings indicate that Akt inhibition may represent a potential therapeutic strategy in T-ALL.
