Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition

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 cel...

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Autores principales:	Thanh-Trang Vo, Lee-or Herzog, Roberta Buono, Jong-Hoon Scott Lee, Sharmila Mallya, Madeleine R. Duong, Joshua Thao, Moran Gotesman, David A. Fruman
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/f6da06c10adf41ed853a873822db0706
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spelling	oai:doaj.org-article:f6da06c10adf41ed853a873822db07062021-11-08T10:47:40ZTargeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition10.1038/s41598-021-00950-y2045-2322https://doaj.org/article/f6da06c10adf41ed853a873822db07062021-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-00950-yhttps://doaj.org/toc/2045-2322Abstract 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.Thanh-Trang VoLee-or HerzogRoberta BuonoJong-Hoon Scott LeeSharmila MallyaMadeleine R. DuongJoshua ThaoMoran GotesmanDavid A. FrumanNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-10 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Thanh-Trang Vo Lee-or Herzog Roberta Buono Jong-Hoon Scott Lee Sharmila Mallya Madeleine R. Duong Joshua Thao Moran Gotesman David A. Fruman Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
description	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.
format	article
author	Thanh-Trang Vo Lee-or Herzog Roberta Buono Jong-Hoon Scott Lee Sharmila Mallya Madeleine R. Duong Joshua Thao Moran Gotesman David A. Fruman
author_facet	Thanh-Trang Vo Lee-or Herzog Roberta Buono Jong-Hoon Scott Lee Sharmila Mallya Madeleine R. Duong Joshua Thao Moran Gotesman David A. Fruman
author_sort	Thanh-Trang Vo
title	Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
title_short	Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
title_full	Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
title_fullStr	Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
title_full_unstemmed	Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition
title_sort	targeting eif4f translation complex sensitizes b-all cells to tyrosine kinase inhibition
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/f6da06c10adf41ed853a873822db0706
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Targeting eIF4F translation complex sensitizes B-ALL cells to tyrosine kinase inhibition

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