Dual inhibition of the mTORC1 and mTORC2 signaling pathways is a promising therapeutic target for Adult T-cell Leukemia

Summary

ATL has a poor prognosis due to severe immunosuppression and rapid tumor progression with resistance to conventional chemotherapy. Recent integrated-genome analysis has revealed mutations in many genes involved in the T-cell signaling pathway, suggesting that the aberration of this pathway is an important factor in ATL pathogenesis and ATL-cell proliferation. We screened a siRNA library to examine signaling-pathway functionality and found that the PI3K/Akt/mTOR pathway is critical to ATL-cell proliferation. We therefore investigated the effect of mTOR inhibitors, including the dual inhibitors PP242 and AZD8055 and the mTORC1 inhibitors rapamycin and everolimus, on HTLV-1-infected-cell and ATL-cell lines. Both dual inhibitors inhibited the proliferation of all tested cell lines by inducing G1-phase cell-cycle arrest and subsequent cell apoptosis, whereas the effects of the two mTORC1 inhibitors were limited, as they did not induce cell apoptosis. In the ATL-cell lines and in the primary ATL samples, both dual inhibitors inhibited phosphorylation of AKT at serine-473, a target of mTORC2, as well as that of S6K, whereas the mTORC1 inhibitors only inhibited mTORC1. Furthermore, AZD8055 more significantly inhibited the in vivo growth of the ATL-cell xenografts than did everolimus. These results indicate that the PI3K/mTOR pathway is critical to ATL-cell proliferation and might thus be a new therapeutic target in ATL.

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