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

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.