Promising Activity of Mammalian Target of Rapamycin Inhibitors in Hematologic Malignancies Therapy

Ota      Fuchs

doi:10.2174/157436211794109460

Abstract

The mammalian target of rapamycin (mTOR) is a downstream mediator of the phosphatidylinositol 3-kinase (PI3K)/Akt (protein kinase B) signaling pathway which regulates cell survival and proliferation. mTOR is a highly conserved serine/threonine protein kinase involved in the contol of cell growth, protein synthesis, and cell cycle progression. The importance of the mTOR pathway has stimulated the development of pharmacological inhibitors of this pathway. The best studied mTOR inhibitor is rapamycin (sirolimus), a natural antibiotic produced by soil bacterium Streptomyces hygroscopicus with antifungal, immunosuppressive and antipoliferative properties. Rapamycin analogues such as CCI-779 (temsirolimus), RAD001 (everolimus) and AP23573 (deforolimus) have a potent antineoplastic effect in many solid tumor models and recent data have also shown their antiproliferative properties in hematological malignancies. Therapeutic trials have been completed or are ongoing for the treatment of acute myeloid leukemia, chronic myeloid leukemia, acute and chronic lymphoid leukemia, lymphoma including mantle cell lymphoma, and multiple myeloma. With an increasing understanding of the feedback loops existing in the PI3K/Akt/mTOR pathway, it has been recognized that inhibition on one output costs at the expense of activation on the other output. Therefore, it is better to inhibit two or more components in this pathway by NVP-BEZ235 (a dual pan-PI3K/mTOR inhibitor) and SF-1126 (inhibitor of all isoforms of PI3K). S9, a novel anticancer agent, a hybrid of α-methylene-γ-lactone and 2-phenyl indole compound which interferes with both PI3K/Akt/mTOR signaling and microtubule cytoskeleton, induces rapid apoptosis and has potent antiproliferative activity in tumor cells. As PI3K inhibitors could impact insulin signaling, diabetes, obesity, and aging, unwanted side effects should be considered.

Keywords: Hematologic malignancies, mammalian target of rapamycin, mTOR inhibitors, phosphatase and tensin homologue tumor suppressor, phosphatidylinositol 3'-kinase, protein kinase B, FKBP12, FRAP1, RAFT1, RAPT1, sirolimus effector protein, CCI-779, RAD001 (everolimus), AP23573 (deforolimus), AML, myelodysplastic syndromes, chronic myelogenous leukemia (CML), AMP-activated protein kinase, 1p36.2, Huntington, elongation factor 3, PP2A, FRB, PRAS40, TSC2, S939, T1462, S6K1, IRS-1, chronic lymphocytic leukemia (CLL), AML, acute T cell leukemias, B-non-Hodgkin's lym-phoma (B-NHL), anaplastic lymphoma kinase, temsirolimus Torisel, everolimus, deforolimus, casein kinase II (CK2), glycogen synthase kinase 3, phosphatidylinositol 4-kinase, P13K, pyridinylfurano-pyrimidine compound PI-103, morpholinylthienopyrimidine, GDC-0941, MEK, p53, mdm2 (murine double minute oncogene, VEGF (vascular endothelial growth factor), topoietic stem cell transplantation (HSCT), graft-versus-host disease, PTEN (the phosphatase and tensin homolog), dexamethasone, sunitinib, HSP 90, ERK inhibitor, lenalidomide, DLBCL, RAD001, retinoblastoma protein, positive anaplastic, chimeric nucleophosmin-ALK, p21(waf1), p27(kip1), c-FLIP, MCL-1, BCL-2, mantle cell lymphoma, tuberous sclerosis, TSC1