Targeting the PI3K/AKT/mTOR signaling axis in children with hematologic malignancies

Abstract

The phosphatidylinositiol 3-kinase (PI3K), AKT, mammalian target of rapamycin (mTOR) signaling pathway (PI3K/AKT/mTOR) is frequently dysregulated in disorders of cell growth and survival, including a number of pediatric hematologic malignancies. The pathway can be abnormally activated in childhood acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), and chronic myelogenous leukemia (CML), as well as in some pediatric lymphomas and lymphoproliferative disorders. Most commonly, this abnormal activation occurs as a consequence of constitutive activation of AKT, providing a compelling rationale to target this pathway in many of these conditions. A variety of agents, beginning with the rapamycin analogue (rapalog) sirolimus, have been used successfully to target this pathway in a number of pediatric hematologic malignancies. Rapalogs demonstrate significant preclinical activity against ALL, which has led to a number of clinical trials. Moreover, rapalogs can synergize with a number of conventional cytotoxic agents and overcome pathways of chemotherapeutic resistance for drugs commonly used in ALL treatment, including methotrexate and corticosteroids. Based on preclinical data, rapalogs are also being studied in AML, CML, and non-Hodgkin's lymphoma. Recently, significant progress has been made using rapalogs to treat pre-malignant lymphoproliferative disorders, including the autoimmune lymphoproliferative syndrome (ALPS); complete remissions in children with otherwise therapy-resistant disease have been seen. Rapalogs only block one component of the pathway (mTORC1), and newer agents are under preclinical and clinical development that can target different and often multiple protein kinases in the PI3K/AKT/mTOR pathway. Most of these agents have been tolerated in early-phase clinical trials. A number of PI3K inhibitors are under investigation. Of note, most of these also target other protein kinases. Newer agents are under development that target both mTORC1 and mTORC2, mTORC1 and PI3K, and the triad of PI3K, mTORC1, and mTORC2. Preclinical data suggest these dual- and multi-kinase inhibitors are more potent than rapalogs against many of the aforementioned hematologic malignancies. Two classes of AKT inhibitors are under development, the alkyl-lysophospholipids (APLs) and small molecule AKT inhibitors. Both classes have agents currently in clinical trials. A number of drugs are in development that target other components of the pathway, including eukaryotic translation initiation factor (eIF) 4E (eIF4E) and phosphoinositide-dependent protein kinase 1 (PDK1). Finally, a number of other key signaling pathways interact with PI3K/AKT/mTOR, including Notch, MNK, Syk, MAPK, and aurora kinase. These alternative pathways are being targeted alone and in combination with PI3K/AKT/mTOR inhibitors with promising preclinical results in pediatric hematologic malignancies. This review provides a comprehensive overview of the abnormalities in the PI3K/AKT/mTOR signaling pathway in pediatric hematologic malignancies, the agents that are used to target this pathway, and the results of preclinical and clinical trials, using those agents in childhood hematologic cancers.

Fig. 1

PI3K/AKT/mT0R signaling pathway. Growth factor or ligand binding to a receptor tyrosine kinase, including IGF-1R, PDGFR, or EGFR, leads to activation of IRS-1 which upregulates and activates PI3K by removing the inhibition of the regulatory (p85) subunit on the catalytic subunit (p110). PI3K can also be directly activated by RTK or RAS. After activation, PI3K phosphorylates PIP₂ to make PIP₃. PIP₃ recruits PDK1 and AKT to the cell membrane. PDK1 and mTORC2 phosphorylate and activate AKT. PTEN negatively regulates AKT activation by converting PIP₃ to PIP₂. Activated AKT can regulate cell growth and protein synthesis by activating mTORC1 through TSC1/2. AKT can stimulate cell-cycle progression by modulating cell-cycle inhibitors (p27^kip1 through FOXO and GSK3) and cell-cycle stimulators (cyclin D1 and c-Myc). AKT can also regulate programmed cell death by inhibition of FasL, BIM, or BAD, and by degradation of p53 through MDM2. mTOR can form two distinct complexes, mTORCI and mTORC2. mTORCI is composed of mTOR, GβL, Mlst8, PRAS40, and raptor. mTORC2 is composed of mTOR, GβL, mSIN1, and Rictor. mTORCI can regulate protein synthesis and cell-cycle progression through phosphorylating p70S6 kinase (S6K1) and 4E-BP1. mTORCI also facilitates the elimination of the p27^kip1 through interactions with p34cdc2, allowing cell-cycle progression by cdks which can phosphorylate Rb. Arrows represent activation. Lines with circles represent inhibition. 4E-BP1 = elF4E binding protein; BAD = BCL-2-associated death promoter; BIM = BCL-2-interacting mediator of cell death; cdks = cyclin-dependent kinases; EGFR = epidermal growth factor receptor; elF = eukaryotic initiation factor; FasL = fas ligand; FOXO = Forkhead box O proteins; GSK3 = glycogen synthase kinase 3; GβL = G protein β subunit-like; IGF-1R = insulin-like growth factor-1 receptor; IRS-1 = insulin receptor substrate-1 ; KIDM2 = mouse double minute 2; Mlst8 = mammalian lethal with sec-13; mSIN1 = mammalian stress-activated protein kinase-interaction protein 1; mTOR = mammalian target of rapamycin; p27^kip1 = cyclin-dependent kinase inhibitor kip1; p34cdc2 = cyclin-dependent controlling kinase p34; PDGFR = platelet-derived growth factor receptor; PDK1 = phosphoinositide-dependent protein kinase 1; PI3K = phosphatidylinositiol 3-kinase; PIP₂ = phosphatidylinositol-4,5-biphosphate; PIP3 = phosphatidylinositol-3,4, 5-triphosphate; PRAS40 = proline-rich AKT substrate of 40 kDa; PROTOR/PRR5 = protein observed with Rictor-1/Proline-rich protein 5; PTEN = phosphatase and tensin homologue deleted on chromosome 10; RAS = a GTPase; Rb = retinoblastoma protein; RTK = receptor tyrosine kinase; TSC1/2 = tuberous sclerosis 1/2 complex.