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Loss of p120ctn causes EGFR-targeted therapy resistance and failure

Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a prime candidate as a therapeutic target. While...

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Autores principales: Landmesser, Mary E., Raup-Konsavage, Wesley M., Lehman, Heather L., Stairs, Douglas B.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592761/
https://www.ncbi.nlm.nih.gov/pubmed/33112928
http://dx.doi.org/10.1371/journal.pone.0241299
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author Landmesser, Mary E.
Raup-Konsavage, Wesley M.
Lehman, Heather L.
Stairs, Douglas B.
author_facet Landmesser, Mary E.
Raup-Konsavage, Wesley M.
Lehman, Heather L.
Stairs, Douglas B.
author_sort Landmesser, Mary E.
collection PubMed
description Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a prime candidate as a therapeutic target. While targeted EGFR therapy is initially effective in 75% of patients, a majority of patients relapse within the first year due to poorly understood mechanisms of resistance. p120-catenin (p120ctn) has recently been implicated as a biomarker for EGFR therapy. In previous studies, we demonstrated that p120ctn is a tumor suppressor and its loss is capable of inducing cancer. Furthermore, p120ctn down-regulation synergizes with EGFR overexpression to cause a highly invasive cell phenotype. The purpose of this present study was to investigate whether p120ctn down-regulation induced EGFR therapeutic resistance. Using human esophageal keratinocytes, we have found that EGFR-targeting compounds are toxic to cells overexpressing EGFR. Interestingly, these therapies do not cause toxicity in cells with EGFR overexpression and decreased p120ctn expression. These data suggest that decreased p120ctn causes resistance to EGFR therapy. We believe these findings are of utmost importance, as there is an unmet need to discover mechanisms of EGFR resistance.
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spelling pubmed-75927612020-11-02 Loss of p120ctn causes EGFR-targeted therapy resistance and failure Landmesser, Mary E. Raup-Konsavage, Wesley M. Lehman, Heather L. Stairs, Douglas B. PLoS One Research Article Epidermal growth factor receptor (EGFR) plays a vital role in cell division and survival signaling pathways. EGFR is activated in nearly every cancer type, and its high expression in tumors is correlated with poor patient outcome. Altogether, EGFR is a prime candidate as a therapeutic target. While targeted EGFR therapy is initially effective in 75% of patients, a majority of patients relapse within the first year due to poorly understood mechanisms of resistance. p120-catenin (p120ctn) has recently been implicated as a biomarker for EGFR therapy. In previous studies, we demonstrated that p120ctn is a tumor suppressor and its loss is capable of inducing cancer. Furthermore, p120ctn down-regulation synergizes with EGFR overexpression to cause a highly invasive cell phenotype. The purpose of this present study was to investigate whether p120ctn down-regulation induced EGFR therapeutic resistance. Using human esophageal keratinocytes, we have found that EGFR-targeting compounds are toxic to cells overexpressing EGFR. Interestingly, these therapies do not cause toxicity in cells with EGFR overexpression and decreased p120ctn expression. These data suggest that decreased p120ctn causes resistance to EGFR therapy. We believe these findings are of utmost importance, as there is an unmet need to discover mechanisms of EGFR resistance. Public Library of Science 2020-10-28 /pmc/articles/PMC7592761/ /pubmed/33112928 http://dx.doi.org/10.1371/journal.pone.0241299 Text en © 2020 Landmesser et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Landmesser, Mary E.
Raup-Konsavage, Wesley M.
Lehman, Heather L.
Stairs, Douglas B.
Loss of p120ctn causes EGFR-targeted therapy resistance and failure
title Loss of p120ctn causes EGFR-targeted therapy resistance and failure
title_full Loss of p120ctn causes EGFR-targeted therapy resistance and failure
title_fullStr Loss of p120ctn causes EGFR-targeted therapy resistance and failure
title_full_unstemmed Loss of p120ctn causes EGFR-targeted therapy resistance and failure
title_short Loss of p120ctn causes EGFR-targeted therapy resistance and failure
title_sort loss of p120ctn causes egfr-targeted therapy resistance and failure
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7592761/
https://www.ncbi.nlm.nih.gov/pubmed/33112928
http://dx.doi.org/10.1371/journal.pone.0241299
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