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HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells

Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To exp...

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Autores principales: McDermott, Martina S. J., Conlon, Neil, Browne, Brigid C., Szabo, Adam, Synnott, Naoise C., O’Brien, Neil A., Duffy, Michael J., Crown, John, O’Donovan, Norma
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406301/
https://www.ncbi.nlm.nih.gov/pubmed/30743996
http://dx.doi.org/10.3390/cancers11020197
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author McDermott, Martina S. J.
Conlon, Neil
Browne, Brigid C.
Szabo, Adam
Synnott, Naoise C.
O’Brien, Neil A.
Duffy, Michael J.
Crown, John
O’Donovan, Norma
author_facet McDermott, Martina S. J.
Conlon, Neil
Browne, Brigid C.
Szabo, Adam
Synnott, Naoise C.
O’Brien, Neil A.
Duffy, Michael J.
Crown, John
O’Donovan, Norma
author_sort McDermott, Martina S. J.
collection PubMed
description Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance.
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spelling pubmed-64063012019-03-21 HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells McDermott, Martina S. J. Conlon, Neil Browne, Brigid C. Szabo, Adam Synnott, Naoise C. O’Brien, Neil A. Duffy, Michael J. Crown, John O’Donovan, Norma Cancers (Basel) Article Prolonged treatment of HER2 positive breast cancer cells with tyrosine kinase inhibitors (TKIs) leads to the emergence of acquired resistance. However, the effects of continuous TKI exposure on cell fate, and the steps leading to the acquisition of a resistant phenotype are poorly understood. To explore this, we exposed five HER2 positive cells lines to HER2 targeted therapies for periods of up to 4 weeks and examined senescence associated β-galactosidase (SA-β-gal) activity together with additional markers of senescence. We found that lapatinib treatment resulted in phenotypic alterations consistent with a senescent phenotype and strong SA-β-gal activity in HER2-positive cell lines. Lapatinib-induced senescence was associated with elevated levels of p15 and p27 but was not dependent on the expression of p16 or p21. Restoring wild type p53 activity either by transfection or by treatment with APR-246, a molecule which reactivates mutant p53, blocked lapatinib-induced senescence and caused increased cell death. In contrast to lapatinib, SA-β-gal activity was not induced by exposing the cells to trastuzumab as a single agent but co-administration of lapatinib and trastuzumab induced senescence, as did treatment of the cells with the irreversible HER2 TKIs neratinib and afatinib. Neratinib- and afatinib-induced senescence was not reversed by removing the drug whereas lapatinib-induced senescence was reversible. In summary, therapy-induced senescence represents a novel mechanism of action of HER2 targeting agents and may be a potential pathway for the emergence of resistance. MDPI 2019-02-08 /pmc/articles/PMC6406301/ /pubmed/30743996 http://dx.doi.org/10.3390/cancers11020197 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
McDermott, Martina S. J.
Conlon, Neil
Browne, Brigid C.
Szabo, Adam
Synnott, Naoise C.
O’Brien, Neil A.
Duffy, Michael J.
Crown, John
O’Donovan, Norma
HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
title HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
title_full HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
title_fullStr HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
title_full_unstemmed HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
title_short HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells
title_sort her2-targeted tyrosine kinase inhibitors cause therapy-induced-senescence in breast cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406301/
https://www.ncbi.nlm.nih.gov/pubmed/30743996
http://dx.doi.org/10.3390/cancers11020197
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