Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors

Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA to facilitate ribosome...

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Autores principales:	Adina Gerson-Gurwitz, Nathan P. Young, Vikas K. Goel, Boreth Eam, Craig R. Stumpf, Joan Chen, Sarah Fish, Maria Barrera, Eric Sung, Jocelyn Staunton, Gary G. Chiang, Kevin R. Webster, Peggy A. Thompson
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	zotatifin eIF4A PI3K AKT mTOR receptor tyrosine kinase Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3c591166c36f4888bb12e979b6ceb351
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spelling	oai:doaj.org-article:3c591166c36f4888bb12e979b6ceb3512021-12-01T08:38:09ZZotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors2234-943X10.3389/fonc.2021.766298https://doaj.org/article/3c591166c36f4888bb12e979b6ceb3512021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.766298/fullhttps://doaj.org/toc/2234-943XOncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5’-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.Adina Gerson-GurwitzNathan P. YoungVikas K. GoelBoreth EamCraig R. StumpfJoan ChenSarah FishMaria BarreraEric SungJocelyn StauntonGary G. ChiangKevin R. WebsterPeggy A. ThompsonFrontiers Media S.A.articlezotatifineIF4API3KAKTmTORreceptor tyrosine kinaseNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	zotatifin eIF4A PI3K AKT mTOR receptor tyrosine kinase Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	zotatifin eIF4A PI3K AKT mTOR receptor tyrosine kinase Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Adina Gerson-Gurwitz Nathan P. Young Vikas K. Goel Boreth Eam Craig R. Stumpf Joan Chen Sarah Fish Maria Barrera Eric Sung Jocelyn Staunton Gary G. Chiang Kevin R. Webster Peggy A. Thompson Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
description	Oncoprotein expression is controlled at the level of mRNA translation and is regulated by the eukaryotic translation initiation factor 4F (eIF4F) complex. eIF4A, a component of eIF4F, catalyzes the unwinding of secondary structure in the 5’-untranslated region (5’-UTR) of mRNA to facilitate ribosome scanning and translation initiation. Zotatifin (eFT226) is a selective eIF4A inhibitor that increases the affinity between eIF4A and specific polypurine sequence motifs and has been reported to inhibit translation of driver oncogenes in models of lymphoma. Here we report the identification of zotatifin binding motifs in the 5’-UTRs of HER2 and FGFR1/2 Receptor Tyrosine Kinases (RTKs). Dysregulation of HER2 or FGFR1/2 in human cancers leads to activation of the PI3K/AKT and RAS/ERK signaling pathways, thus enhancing eIF4A activity and promoting the translation of select oncogenes that are required for tumor cell growth and survival. In solid tumor models driven by alterations in HER2 or FGFR1/2, downregulation of oncoprotein expression by zotatifin induces sustained pathway-dependent anti-tumor activity resulting in potent inhibition of cell proliferation, induction of apoptosis, and significant in vivo tumor growth inhibition or regression. Sensitivity of RTK-driven tumor models to zotatifin correlated with high basal levels of mTOR activity and elevated translational capacity highlighting the unique circuitry generated by the RTK-driven signaling pathway. This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.
format	article
author	Adina Gerson-Gurwitz Nathan P. Young Vikas K. Goel Boreth Eam Craig R. Stumpf Joan Chen Sarah Fish Maria Barrera Eric Sung Jocelyn Staunton Gary G. Chiang Kevin R. Webster Peggy A. Thompson
author_facet	Adina Gerson-Gurwitz Nathan P. Young Vikas K. Goel Boreth Eam Craig R. Stumpf Joan Chen Sarah Fish Maria Barrera Eric Sung Jocelyn Staunton Gary G. Chiang Kevin R. Webster Peggy A. Thompson
author_sort	Adina Gerson-Gurwitz
title	Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
title_short	Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
title_full	Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
title_fullStr	Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
title_full_unstemmed	Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors
title_sort	zotatifin, an eif4a-selective inhibitor, blocks tumor growth in receptor tyrosine kinase driven tumors
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3c591166c36f4888bb12e979b6ceb351
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Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors

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