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.
Highlights
The mechanistic target of rapamycin is a kinase whose activation is associated with poor prognosis in pre-B cell acute lymphoblastic leukemia (B-ALL)
The cytotoxic effect of that mTOR kinase inhibitors (TOR-KI) compound MLN0128 inhibition is fully recapitulated by selective mTORC1 kinase inhibitors (RapaLinks) or by genetic reactivation of 4E-BP1. (A) Schematic diagram of the Phosphoinositide 3-kinases (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway, downstream mTORC1 effectors, and small molecule inhibitors used in this study
Notes: RapaLinks strongly inhibit mTORC1, and only inhibit mTORC2 at high concentrations; SBI756 disrupts binding of eIF4G to eIF4E; silvestrol reduces the pool of free eIF4A by stabilizing its binding to mRNA; hippuristanol inhibits the helicase activity of eIF4A. (B) Western blot of p190 cells treated with TOR-KI (MLN0128, 10 nM (Fig. 4A). MLN0128 (100 nM)), rapamycin (10 nM), or two RapaLink compounds (0.1–10 nM range) for 24 h
Summary
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. 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 eIF4Ftargeted molecules in combination therapies with TKIs in B-ALL and other blood cancers.
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