Cargando…
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...
Autores principales: | , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663026/ https://www.ncbi.nlm.nih.gov/pubmed/34900714 http://dx.doi.org/10.3389/fonc.2021.766298 |
_version_ | 1784613556548796416 |
---|---|
author | Gerson-Gurwitz, Adina Young, Nathan P. Goel, Vikas K. Eam, Boreth Stumpf, Craig R. Chen, Joan Fish, Sarah Barrera, Maria Sung, Eric Staunton, Jocelyn Chiang, Gary G. Webster, Kevin R. Thompson, Peggy A. |
author_facet | Gerson-Gurwitz, Adina Young, Nathan P. Goel, Vikas K. Eam, Boreth Stumpf, Craig R. Chen, Joan Fish, Sarah Barrera, Maria Sung, Eric Staunton, Jocelyn Chiang, Gary G. Webster, Kevin R. Thompson, Peggy A. |
author_sort | Gerson-Gurwitz, Adina |
collection | PubMed |
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 | Online Article Text |
id | pubmed-8663026 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-86630262021-12-11 Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors Gerson-Gurwitz, Adina Young, Nathan P. Goel, Vikas K. Eam, Boreth Stumpf, Craig R. Chen, Joan Fish, Sarah Barrera, Maria Sung, Eric Staunton, Jocelyn Chiang, Gary G. Webster, Kevin R. Thompson, Peggy A. Front Oncol Oncology 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. Frontiers Media S.A. 2021-11-24 /pmc/articles/PMC8663026/ /pubmed/34900714 http://dx.doi.org/10.3389/fonc.2021.766298 Text en Copyright © 2021 Gerson-Gurwitz, Young, Goel, Eam, Stumpf, Chen, Fish, Barrera, Sung, Staunton, Chiang, Webster and Thompson https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Gerson-Gurwitz, Adina Young, Nathan P. Goel, Vikas K. Eam, Boreth Stumpf, Craig R. Chen, Joan Fish, Sarah Barrera, Maria Sung, Eric Staunton, Jocelyn Chiang, Gary G. Webster, Kevin R. Thompson, Peggy A. Zotatifin, an eIF4A-Selective Inhibitor, Blocks Tumor Growth in Receptor Tyrosine Kinase Driven Tumors |
title | 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_short | 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 |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663026/ https://www.ncbi.nlm.nih.gov/pubmed/34900714 http://dx.doi.org/10.3389/fonc.2021.766298 |
work_keys_str_mv | AT gersongurwitzadina zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT youngnathanp zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT goelvikask zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT eamboreth zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT stumpfcraigr zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT chenjoan zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT fishsarah zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT barreramaria zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT sungeric zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT stauntonjocelyn zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT chianggaryg zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT websterkevinr zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors AT thompsonpeggya zotatifinaneif4aselectiveinhibitorblockstumorgrowthinreceptortyrosinekinasedriventumors |