Type

Journal Article

Authors

Norma O'Donovan
John Crown
Michael J Duffy
Neil A O'Brien
Naoise C Synnott
Adam Szabo
Brigid C Browne
Neil Conlon
Martina S J McDermott

Subjects

Biochemistry

Topics
cell death tyrosine kinase cell lines her2 positive breast cancer cancer therapy cancer cells inhibitors

HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells. (2019)

Abstract 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.
Collections Ireland -> Dublin City University -> PubMed

Full list of authors on original publication

Norma O'Donovan, John Crown, Michael J Duffy, Neil A O'Brien, Naoise C Synnott, Adam Szabo, Brigid C Browne, Neil Conlon, Martina S J McDermott

Experts in our system

1
Norma O'Donovan
Dublin City University
Total Publications: 59
 
2
John Crown
Dublin City University
Total Publications: 104
 
3
Michael J Duffy
University College Dublin
 
4
Neil A O'Brien
Dublin City University
Total Publications: 9
 
5
Naoise C Synnott
Dublin City University
 
6
Brigid C Browne
Dublin City University
Total Publications: 11
 
7
Neil T. Conlon
Dublin City University
Total Publications: 10
 
8
Martina S J McDermott
Dublin City University
Total Publications: 9