Perspectives on inhibiting mTOR as a future treatment strategy for hematological malignancies

Targeted inhibition of mTORC1 and mTORC2 by active-site mTOR inhibitors has cytotoxic effects in T-cell acute lymphoblastic leukemia

“…39 At present, the new frontier of mTOR inhibition is represented by the use of active site mTOR inhibitors, which target both mTORC1 and mTORC2, without affecting PI3K activity. 9 Accordingly, in our current study we tested the anti-leukemic activity of three compounds that directly target the mTOR catalytic domain. Two of these compounds (PP-242 and OSI-027) have already been tested in other hematological cancers, including Philadelphia þ acute leukemias 39,40 and multiple myeloma, 41 and promising preclinical data were reported.…”

“…8 mTORC2 is usually considered to be rapamycin resistant. 9 Both mTORC1 and mTORC2 are activated in most of T-ALL patients underscoring these complexes as major targets for T-ALL treatment. 10 mTORC1/mTORC2 activation in T-ALL usually depends on upregulation of the phosphatidylinositol 3-kinase (PI3K)/Akt axis, which is a common event in T-ALL patients 11 and has a negative impact on prognosis.…”

Targeting the translational apparatus to improve leukemia therapy: roles of the PI3K/PTEN/Akt/mTOR pathway

“…Thus, targeting mTOR more globally is becoming an important therapeutic option in AML therapy. 139,[143][144][145][146][147] Studies by other investigators performing high-throughput screening assays have identified 4EGI-1, which is a 4E-BP1 mimetic and a potent inhibitor of the interactions between eIF4E and eIF4G. The inhibitor 4EGI-1 has been shown in some systems to inhibit the growth of BCR-ABL-transformed Ba/F3 hematopoietic cells, but not the parental interleukin-3-dependent cells line (Ba/F3).…”

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

“…10 mTORC2, defined by the interaction between mTOR and Rictor (rapamycin-insensitive companion of mTOR), is considered to be rapamycin resistant and phosphorylates Akt at Ser 473, one of two phosphorylated residues required for full Akt activation. 10 Upregulated mTORC1 activity within cancer cells increases the synthesis of many oncogenic proteins controlled at the translation initiation level, through the phosphorylation of the physiologic translation repressor 4E-BP1 at multiple residues. 11, 12 An important regulator of the mTORC1-dependent translation process is the liver kinase B1 (LKB1)/AMP-activated protein kinase (AMPK) axis.…”