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Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis

The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resi...

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Autores principales: Kadry, Yasmin A., Lee, Jia-Ying, Witze, Eric S.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492172/
https://www.ncbi.nlm.nih.gov/pubmed/34610265
http://dx.doi.org/10.1098/rsob.210033
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author Kadry, Yasmin A.
Lee, Jia-Ying
Witze, Eric S.
author_facet Kadry, Yasmin A.
Lee, Jia-Ying
Witze, Eric S.
author_sort Kadry, Yasmin A.
collection PubMed
description The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells. In this review, we discuss our recent discovery that the palmitoyltransferase DHHC20 palmitoylates EGFR on the C-terminal domain and plays a critical role in signal regulation during oncogenesis. Inhibiting DHHC20 expression or mutating the palmitoylation site on EGFR alters the EGF-induced signalling kinetics from a transient signal to a sustained signal. The change in signalling is accompanied by a decrease in cell proliferation in multiple human cancer cell lines. Our in vivo studies demonstrate that ablating the gene Zdhhc20 by CRISPR/Cas9-mediated inhibition in a mouse model of oncogenic Kras-driven lung adenocarcinoma potently inhibits tumorigenesis. The negative effect on tumorigenesis is mediated by EGFR since the expression of a palmitoylation-resistant mutant form of EGFR also inhibits Kras-driven lung adenocarcinoma. Finally, reducing EGFR palmitoylation increases the sensitivity of multiple cancer cell lines to existing inhibitors of EGFR and downstream signalling effector pathways. We will discuss the implications of these effects and strategies for targeting these new vulnerabilities.
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spelling pubmed-84921722021-10-29 Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis Kadry, Yasmin A. Lee, Jia-Ying Witze, Eric S. Open Biol Review The epidermal growth factor receptor (EGFR) is an essential driver of oncogenic signalling, and EGFR inhibitors are some of the earliest examples of successful targeted therapies in multiple types of cancer. The tractability of EGFR as a therapeutic target is overshadowed by the inevitable drug resistance that develops. Overcoming resistance mechanisms requires a deeper understanding of EGFR regulation in cancer cells. In this review, we discuss our recent discovery that the palmitoyltransferase DHHC20 palmitoylates EGFR on the C-terminal domain and plays a critical role in signal regulation during oncogenesis. Inhibiting DHHC20 expression or mutating the palmitoylation site on EGFR alters the EGF-induced signalling kinetics from a transient signal to a sustained signal. The change in signalling is accompanied by a decrease in cell proliferation in multiple human cancer cell lines. Our in vivo studies demonstrate that ablating the gene Zdhhc20 by CRISPR/Cas9-mediated inhibition in a mouse model of oncogenic Kras-driven lung adenocarcinoma potently inhibits tumorigenesis. The negative effect on tumorigenesis is mediated by EGFR since the expression of a palmitoylation-resistant mutant form of EGFR also inhibits Kras-driven lung adenocarcinoma. Finally, reducing EGFR palmitoylation increases the sensitivity of multiple cancer cell lines to existing inhibitors of EGFR and downstream signalling effector pathways. We will discuss the implications of these effects and strategies for targeting these new vulnerabilities. The Royal Society 2021-10-06 /pmc/articles/PMC8492172/ /pubmed/34610265 http://dx.doi.org/10.1098/rsob.210033 Text en © 2021 The Authors. https://creativecommons.org/licenses/by/4.0/Published by the Royal Society under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, provided the original author and source are credited.
spellingShingle Review
Kadry, Yasmin A.
Lee, Jia-Ying
Witze, Eric S.
Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
title Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
title_full Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
title_fullStr Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
title_full_unstemmed Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
title_short Regulation of EGFR signalling by palmitoylation and its role in tumorigenesis
title_sort regulation of egfr signalling by palmitoylation and its role in tumorigenesis
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8492172/
https://www.ncbi.nlm.nih.gov/pubmed/34610265
http://dx.doi.org/10.1098/rsob.210033
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