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

1
Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA
2
Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, 9 Dublin, Ireland
3
UCD School of Medicine and Medical Science, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, 4 Dublin, Ireland
4
UCD Clinical Research Centre, St. Vincent’s University Hospital, 4 Dublin, Ireland
5
Department of Medical Oncology, St. Vincent’s University Hospital, Elm Park, 4 Dublin, Ireland
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(2), 197; https://doi.org/10.3390/cancers11020197
Received: 15 January 2019 / Accepted: 1 February 2019 / Published: 8 February 2019
(This article belongs to the Special Issue Cellular Stress in Cancer Progression, Drug Resistance and Treatment)
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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. View Full-Text
Keywords: lapatinib; HER2; breast cancer; TKI; erbB2; senescence; neratinib; afatinib; trastuzumab lapatinib; HER2; breast cancer; TKI; erbB2; senescence; neratinib; afatinib; trastuzumab
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McDermott, M.S.J.; Conlon, N.; Browne, B.C.; Szabo, A.; Synnott, N.C.; O’Brien, N.A.; Duffy, M.J.; Crown, J.; O’Donovan, N. HER2-Targeted Tyrosine Kinase Inhibitors Cause Therapy-Induced-Senescence in Breast Cancer Cells. Cancers 2019, 11, 197.

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