Dual Inhibition of Class IA Phosphatidylinositol 3-Kinase and Mammalian Target of Rapamycin as a New Therapeutic Option for T-Cell Acute Lymphoblastic Leukemia

Abstract

Recent investigations have documented that constitutively activated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian Target of Rapamycin (mTOR) signaling is a common feature of T-cell acute lymphoblastic leukemia (T-ALL) where it strongly influences growth and survival. These findings lend compelling weight for the application of PI3K/Akt/mTOR inhibitors in T-ALL. However, our knowledge of PI3K/Akt/mTOR signaling in T-ALL is limited and it is not clear whether it could be an effective target for innovative therapeutic strategies. Here, we have analyzed the therapeutic potential of the dual PI3K/mTOR inhibitor, PI-103, a small synthetic molecule of the pyridofuropyrimidine class, on both T-ALL cell lines and patient samples, which displayed constitutive activation of PI3K/Akt/mTOR signaling. PI-103 inhibited the growth of T-ALL cells, including 170-kDa glycoprotein overexpressing cells. PI-103 cytotoxicity was independent of p53 gene status. PI-103 was more potent than inhibitors which are selective only for PI3K (Wortmannin, LY294002) or for mTOR (rapamycin). PI-103 induced G0/G1 phase cell cycle arrest and apoptosis which was characterized by activation of caspase-3 and -9. PI-103 caused Akt dephosphorylation, accompanied by dephosphorylation of the Akt downstream target, glycogen synthase kinase-3β. Also mTOR downstream targets were dephosphorylated in response to PI-103, including p70S6 kinase, ribosomal S6 protein, and 4E-BP1. PI-103 strongly synergized with vincristine. These findings indicate that multi-targeted therapy towards PI3K and mTOR, alone or with existing drugs, may serve as an efficient treatment towards T-ALL cells which require upregulation of PI3K/Akt/mTOR signaling for their survival and growth.

AMP-dependent kinase/mammalian target of rapamycin complex 1 signaling in T-cell acute lymphoblastic leukemia: therapeutic implications

“…In preclinical models of T-ALL, the efficacy of the mTORC1 inhibitor, rapamycin, appears weak, at least in monotherapy settings. 41 Indeed, allosteric mTORC1 inhibitors such as rapamycin and its derivatives do not target 4E-BP1 in T-ALL cells and this limits their efficacy. 12 In this study, we tested the anti-leukemic activity of metformin on T-ALL cells, as recent data have highlighted that this drug targets 4E-BP1-dependent translation in AML.…”

Targeting the PI3K/AKT/mTOR Signaling Axis in Children with Hematologic Malignancies

“…[29,154,155] Dual inhibition of PI3K and mTORC1, however, using either a PI3K inhibitor with a rapalog or an agent that targets both (e.g. PI-103) is superior to PI3K inhibitors or rapalogs alone in preclinical models.…”

“…PI-103) is superior to PI3K inhibitors or rapalogs alone in preclinical models. [29,154] Furthermore, the dual mTORC1/2 inhibitors PP242 and OSI-027 are very active in vitro against pre-clinical models of pre-T-ALL (cell lines and primary cells) and are superior to rapalogs as these agents successfully inactivate AKT and mTOR. [156] BEZ235, an inhibitor of mTORC1/2 and PI3K, was also shown to be very active against pre-T-ALL in vitro, inactivating both AKT and mTOR.…”

PI3K inhibitors prime neuroblastoma cells for chemotherapy by shifting the balance towards pro-apoptotic Bcl-2 proteins and enhanced mitochondrial apoptosis

“…There are so far only few studies using PI3K inhibitors as chemosensitizers, for example in T-cell acute lymphoblastic leukemia (Chiarini et al, 2009), glioblastoma (Guillard et al, 2009;Westhoff et al, 2009) or chronic lymphocytic leukemia (Niedermeier et al, 2009), and little is yet known about the underlying molecular mechanisms of sensitization. Thus, the novelty of our study resides in particular in the elucidation of the molecular events mediating the cooperative cytotoxicity of the recently developed PI3K inhibitor PI103 and anticancer drugs, such as Doxorubicin, by demonstrating that chemosensitization by PI103 critically depends on mitochondrial outer membrane permeabilization as the result of a shift towards pro-apoptotic Bcl-2 proteins.…”