ABSTRACT
The mechanistic target of rapamycin (mTOR) is a kinase whose activation is associated with poor prognosis in pre-B cell acute lymphoblastic leukemia (B-ALL). These and other findings have prompted diverse strategies for targeting mTOR signaling in B-ALL and other B-cell malignancies. In cellular models of Philadelphia Chromosome-positive (Ph+) B-ALL, mTOR kinase inhibitors (TOR-KIs) that inhibit both mTOR-complex-1 (mTORC1) and mTOR-complex-2 (mTORC2) enhance the cytotoxicity of tyrosine kinase inhibitors (TKIs) such as dasatinib. However, TOR-KIs have not shown substantial efficacy at tolerated doses in blood cancer clinical trials. Selective inhibition of mTORC1 or downstream effectors provides alternative strategies that may improve selectivity towards leukemia cells. Of particular interest is the eukaryotic initiation factor 4F (eIF4F) complex that mediates cap-dependent translation. Here we use novel chemical and genetic approaches to show that selective targeting of either mTORC1 kinase activity or components of the eIF4F complex sensitizes murine BCR-ABL-dependent pre-B leukemia cells to dasatinib. SBI-756, a small molecule inhibitor of eIF4F assembly, sensitizes human Ph+ and Ph-like B-ALL cells to dasatinib cytotoxicity without affecting survival of T lymphocytes or natural killer cells. These findings support the further evaluation of eIF4F-targeted molecules in combination therapies with TKIs in B-ALL and other blood cancers.
Subject(s)
Eukaryotic Initiation Factor-4F/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/physiopathology , Animals , Cell Line, Tumor , Dasatinib/pharmacology , Eukaryotic Initiation Factor-4F/physiology , Imatinib Mesylate/pharmacology , Mechanistic Target of Rapamycin Complex 1 , Mechanistic Target of Rapamycin Complex 2 , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Knockout , Phosphorylation , Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Protein Kinase Inhibitors/pharmacology , Protein-Tyrosine Kinases , Pyrimidines/pharmacology , Signal Transduction/drug effects , TOR Serine-Threonine KinasesABSTRACT
Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulator of cell growth, division and survival. Many haematologic malignancies exhibit elevated or aberrant mTOR activation, supporting the launch of numerous clinical trials aimed at evaluating the potential of single agent mTOR-targeted therapies. While promising early clinical data using allosteric mTOR inhibitors (rapamycin and its derivatives, rapalogs) have suggested activity in a subset of haematologic malignancies, these agents have shown limited efficacy in most contexts. Whether the efficacy of these partial mTOR inhibitors might be enhanced by more complete target inhibition is being actively addressed with second generation ATP-competitive mTOR kinase inhibitors (TOR-KIs), which have only recently entered clinical trials. However, emerging preclinical data suggest that despite their biochemical advantage over rapalogs, TOR-KIs may retain a primarily cytostatic response. Rather, combinations of mTOR inhibition with other targeted therapies have demonstrated promising efficacy in several preclinical models. This review investigates the current status of rapalogs and TOR-KIs in B cell malignancies, with an emphasis on emerging preclinical evidence of synergistic combinations involving mTOR inhibition.
