cular Pathways R get of Rapamycin Signaling in Leukemia and Lymphoma

wnloaded wth factors and many oncogenes activate the lipid kinase phosphoinositide 3-kinase (PI3K), ing a signaling cascade that includes the protein kinases AKT and target of rapamycin (TOR). The AKT/TOR signaling pathway is a significant contributor to disease in various human cancers, includmatologic malignancies. Here we discuss different strategies to inhibit TOR for the treatment of ia, lymphoma, and myeloma. The TOR enzyme exists in two complexes in cells, TORC1 and 2. The majority of preclinical and clinical efforts to target TOR have involved using rapamycin s analogs (rapalogs), which suppress TORC1 only partially and do not acutely inhibit TORC2. class of small molecules targeting the ATP-binding site of the TOR kinase, termed active-site inhibitors (asTORi), achieves greater inhibition of both TOR complexes, resulting in broader ession of the PI3K/AKT/TOR signaling network. Preclinical evidence suggests that asTORi have r efficacy than rapalogs in Philadelphia chromosome–positive acute lymphoblastic leukemia and ell lymphoma. These agents also show greater tolerability in animal models relative to rapalogs or in T-c inhibitors of PI3K. These findings encourage broader evaluation of asTORi efficacy in acute myeloid leukemia, B-cell lymphoma, myeloma, and other blood cancers. Clin Cancer Res; 16(22); 5374–80. ©2010 AACR.