mTORC1 inhibition activates PI3K/Akt by up-regulating IGF-1R signaling in acute myeloid leukemia: rational for therapeutic inhibition of both pathways

The PI3K/Akt and mTORC1 pathways are frequently activated, representing potential therapeutic targets in acute myeloid leukaemia (AML). In 19 AML samples with constitutive PI3K/Akt activation, the rapamycin derivative inhibitor everolimus (RAD001) increased Akt phosphorylation. This mTORC1-mediated Akt up-regulation was explained by an IGF-1/IGF1 receptor autocrine loop: a/ blast cells expressed functional IGF-1 receptors, and IGF-1induced Akt activation was increased by RAD001, b/ a neutralizing anti-IGF-1R alpha-IR3 monoclonal antibody reversed the RAD001-induced Akt phosphorylation, c/ autocrine production of IGF-1 was detected in purified blast cells by quantitative RT-PCR and immunofluorescence. This RAD001-induced PI3K/Akt upregulation was due to an upregulated expression of the IRS2 adaptor. Finally, we observed that concomitant inhibition of mTORC1 and PI3K/Akt by RAD001 and IC87114 induced additive anti-proliferative effects. Our results suggest that dual inhibition of the mTORC1 complex and the IGF-1/IGF1R/PI3K/Akt pathway in AML may enhance the efficacy of mTOR inhibitors in treatment of this disease. For personal use only. on October 22, 2017. by guest www.bloodjournal.org From