Functional characterization of the PI3K/AKT/MTOR signaling pathway for targeted therapy in B-precursor acute lymphoblastic leukemia

Abstract

B-cell precursor acute lymphoblastic leukemias (B-ALL) are characterized by the activation of signaling pathways, which are involved in survival and proliferation of leukemia cells. Using an unbiased shRNA library screen enriched for targeting signaling pathways, we identified MTOR as the key gene on which human B-ALL E2A-PBX1+ RCH-ACV cells are dependent. Using genetic and pharmacologic approaches, we investigated whether B-ALL cells depend on MTOR upstream signaling pathways including PI3K/AKT and the complexes MTORC1 or MTORC2 for proliferation and survival in vitro and in vivo. Notably, the combined inhibition of MTOR and AKT shows a synergistic effect on decreased cell proliferation in B-ALL with different karyotypes. Hence, B-ALL cells were more dependent on MTORC2 rather than MTORC1 complex in genetic assays. Using cell metabolomics, we identified changes in mitochondrial fuel oxidation after shRNA-mediated knockdown or pharmacological inhibition of MTOR. Dependence of the cells on fatty acid metabolism for their energy production was increased upon inhibition of MTOR and associated upstream signaling pathways, disclosing a possible target for a combination therapy. In conclusion, B-ALL are dependent on the PI3K/AKT/MTOR signaling pathway and the combination of specific small molecules targeting this pathway appears to be promising for the treatment of B-ALL patients.