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Adult T‐cell leukemia ( ATL ) has a poor prognosis as a result of 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 si RNA  library to examine signaling‐pathway functionality and found that the  PI 3K/Akt/ mTOR  pathway is critical to  ATL ‐cell proliferation. We therefore investigated the effect of mammalian target of rapamycin ( mTOR ) inhibitors, including the dual inhibitors  PP 242 and  AZD 8055 and the  mTORC 1 inhibitors rapamycin and everolimus, on human T‐cell leukemia virus type 1 ( 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 2  mTORC 1 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  mTORC 2, as well as that of S6K, whereas the  mTORC 1 inhibitors only inhibited  mTORC 1. Furthermore,  AZD 8055 more significantly inhibited the in vivo growth of the  ATL ‐cell xenografts than did everolimus. These results indicate that the  PI 3K/ mTOR  pathway is critical to  ATL ‐cell proliferation and might thus be a new therapeutic target in ATL.

Dual inhibition of the mTORC 1 and mTORC 2 signaling pathways is a promising therapeutic target for adult T‐cell leukemia