Irreversible panHER tyrosine kinase inhibitors (TKIs) to induce irreversible senescence in HER2 positive breast cancer cells.

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e12092-e12092 ◽  
Author(s):  
Martina McDermott ◽  
Brigid Browne ◽  
Adam Szabo ◽  
John Crown ◽  
Norma O'Donovan
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

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

Cancers ◽  
2019 ◽  
Vol 11 (2) ◽  
pp. 197 ◽  
Author(s):  
Martina S.J. McDermott ◽  
Neil Conlon ◽  
Brigid C. Browne ◽  
Adam Szabo ◽  
Naoise C. Synnott ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Cell Fate ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Prolonged Treatment ◽  
Her2 Positive

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.

scholarly journals Targeting the EphB4 receptor tyrosine kinase sensitizes HER2-positive breast cancer cells to Lapatinib

2020 ◽  
Vol 475 ◽  
pp. 53-64 ◽  
Author(s):  
Jinlei Ding ◽  
Yating Yao ◽  
Gena Huang ◽  
Xiaonan Wang ◽  
Jingyan Yi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Receptor Tyrosine Kinase ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

HER-targeted tyrosine kinase inhibitors enhance response to trastuzumab and pertuzumab in HER2-positive breast cancer

2018 ◽  
Vol 37 (3) ◽  
pp. 441-451 ◽  
Author(s):  
Alexandra Canonici ◽  
Laura Ivers ◽  
Neil T. Conlon ◽  
Kasper Pedersen ◽  
Nicola Gaynor ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer

Recent Updates on the Therapeutic Potential of HER2 Tyrosine Kinase Inhibitors for the Treatment of Breast Cancer

2018 ◽  
Vol 18 (4) ◽  
pp. 306-327 ◽  
Author(s):  
Heena Singla ◽  
Anjana Munshi ◽  
Raja Paramjit Singh Banipal ◽  
Vinod Kumar
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Therapeutic Potential ◽  
Her2 Receptor ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Development Of Resistance ◽  
Positive Breast Cancer

HER2 positive breast cancer is characterized by the low survival rate in the metastatic patients. Development of resistance and disease-relapse are the major problems associated with the currently available therapies for HER2 positive breast cancer. There are two major targeted therapies for HER2 positive breast cancer viz. monoclonal antibodies and tyrosine-kinase inhibitors, and both of these therapies have their advantages and limitations. To address the limitations associated with the existing therapies, use of antibodies and TKIs as combination therapy proved to be more effective. Various chemical modifications can be performed on tyrosine-kinase inhibitors to develop novel ligands with increased selectivity for HER2 kinase. A number of tyrosine-kinase inhibitors are in various phases of clinical trials for the treatment of HER2 positive breast cancer. In the current review article, recent developments on various HER2 tyrosine-kinase inhibitors have been reported. Various structurally different scaffolds bind to the HER2 receptor and exhibit potent anti-cancer activities. The structural and pharmacophoric requirements of the scaffolds are discussed in detail so as to discover effective drug candidates for the treatment of HER2 positive breast cancer.

Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells

2010 ◽  
Vol 29 (5) ◽  
pp. 752-759 ◽  
Author(s):  
Norma O’Donovan ◽  
Annette T. Byrne ◽  
Aisling E. O’Connor ◽  
Sharon McGee ◽  
William M. Gallagher ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tyrosine Kinase ◽  
Cancer Cells ◽  
Tyrosine Kinase Inhibitors ◽  
Breast Cancer Cells ◽  
Kinase Inhibitors ◽  
Synergistic Interaction ◽  
Her 2 ◽  
Positive Breast Cancer

scholarly journals UCP-2 inhibitor enhanced the efficacy of trastuzumab against HER2 positive breast cancer cells

2021 ◽  
Author(s):  
Jun Hua ◽  
Zhe Zhang ◽  
Lili Zhang ◽  
Yan Sun ◽  
Yuan Yuan
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Neoadjuvant Therapy ◽  
Needle Biopsy ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Trastuzumab Treatment ◽  
Her2 Positive Breast Cancer ◽  
Trastuzumab Therapy ◽  
Positive Breast Cancer

Abstract Purpose This study aimed to investigate the possibility of UCP-2 inhibitor in reducing acquired resistance of trastuzumab to improve the outcome of patients receiving trastuzumab therapy by exploring the relationship between UCP-2 expression and HER2 signaling pathway and examining whether UCP-2 expression was modulated by trastuzumab treatment. Methods 32 women diagnosed with primary HER2-positive breast cancer were recruited in this study. Needle biopsy was obtained from patients before they received at least four cycles neoadjuvant therapy containing trastuzumab in combination with chemotherapy. Surgical tumor biopsy was obtained during surgical procedure after the neoadjuvant therapy. Levels of HER2 phosphorylation and UCP-2 expression were detected by immunohistochemistry (IHC) and compared between tumor needle biopsy tissue and surgical tumor samples of these patients, as well as in BT474 breast cancer cells before and after trastuzumab treatment. HER2-selective phosphorylation/kinase activity inhibitor ONT-380 was used to identify the correlation between HER2 phosphorylation level and UCP-2 expression. UCP-2 inhibitor Genipin was then used to evaluate the apoptosis index in BT474 cells treated with trastuzumab. Results UCP-2 expression was significantly elevated in surgical tumor samples from breast cancer patients receiving trastuzumab in a neoadjuvant setting. We further confirmed our findings in HER2-positive BT474 cell line and found that trastuzumab treatment induced phosphorylation of HER2 and the overexpression of UCP-2, and the latter can be reversed by HER2 selective kinase inhibitor ONT-380. Moreover, UCP-2 inhibitor Genipin significantly enhanced the proliferation suppression effects of trastuzumab and markedly promoted apoptosis. Conclusion Taken together, our study identified UCP-2 as a novel therapeutic target for HER2 positive breast cancer and UCP-2 inhibitor may have great potential to enhance the response rate and efficacy of trastuzumab therapy.

scholarly journals Dual inhibition of IGF1R and ER enhances response to trastuzumab in HER2 positive breast cancer cells

2017 ◽  
Vol 50 (6) ◽  
pp. 2221-2228 ◽  
Author(s):  
Martina S.J. Mcdermott ◽  
Alexandra Canonici ◽  
Laura Ivers ◽  
Brigid C. Browne ◽  
Stephen F. Madden ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Dual Inhibition ◽  
Positive Breast Cancer

scholarly journals Linc01638 Promotes Tumorigenesis in HER2+ Breast Cancer

2018 ◽  
Vol 19 (1) ◽  
pp. 74-80 ◽  
Author(s):  
Peng Liu ◽  
Hailin Tang ◽  
Jiali Wu ◽  
Xingsheng Qiu ◽  
Yanan Kong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Apoptosis ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Mouse Xenograft ◽  
Her2 Positive Breast Cancer ◽  
Mouse Xenograft Model ◽  
Positive Breast Cancer

Background: Long non-coding RNAs play crucial roles in various biological activities and diseases. The role of long intergenic non-coding RNA01638 (linc01638) in breast cancer, especially in HER2-positive breast cancer, remains largely unknown. Objective: To investigate the effect of linc01638 on tumorigenesis in HER2-positive breast cancer. </P><P> Methods: We first used qRT-PCR to detect linc01638 expression in HER2-positive breast cancer cells and tissues. Then we analyzed the effects of linc01638 expression in HER2-positive breast cancer cells through cell apoptosis assay, cell proliferation assay, colony formation assay, and cell invasion assay. We conducted mouse xenograft model to further confirm the role of linc01638 in HER2-positive breast cancer. Moreover, we used Western blot and IHC analysis to access the effect of linc01638 on DNMTs, BRCA1 and PTEN expressions in transplanted tumors. Results: Linc01638 was found to be remarkably overexpressed in HER2-positive breast cancer cells and tissues. Suppression of linc01638 enhanced cell apoptosis, as well as inhibited the growth and invasiveness of HER2-positive breast cancer cells in vitro and tumor progression and metastasis in vivo. Furthermore, inhibition of linc01638 by shRNA attenuated expression of DNMT1, DNMT3a, and DNMT3b, and promoted expression of BRCA1 and PTEN in HER2-positive breast cancer cells and mouse xenograft models. Linc01638 might be a promising biomarker and therapeutic target for treatment of HER2-positive breast cancer.

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