Abstract 2107: Identification of alternative compounds by drug screening of HER2 positive breast cancer cell lines.

2013 ◽  
Author(s):  
Sandra Nyberg ◽  
Vesa Hongisto ◽  
Dagim Shiferaw Tadele ◽  
Henrik Edgren ◽  
Suvi-Katri Leivonen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Drug Screening ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

scholarly journals RANK signaling increases after anti-HER2 therapy contributing to the emergence of resistance in HER2-positive breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Adrián Sanz-Moreno ◽  
Sonia Palomeras ◽  
Kim Pedersen ◽  
Beatriz Morancho ◽  
Tomas Pascual ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Rank Signaling ◽  
Positive Breast Cancer

Abstract Background Around 15–20% of primary breast cancers are characterized by HER2 protein overexpression and/or HER2 gene amplification. Despite the successful development of anti-HER2 drugs, intrinsic and acquired resistance represents a major hurdle. This study was performed to analyze the RANK pathway contribution in HER2-positive breast cancer and anti-HER2 therapy resistance. Methods RANK and RANKL protein expression was assessed in samples from HER2-positive breast cancer patients resistant to anti-HER2 therapy and treatment-naive patients. RANK and RANKL gene expression was analyzed in paired samples from patients treated with neoadjuvant dual HER2-blockade (lapatinib and trastuzumab) from the SOLTI-1114 PAMELA trial. Additionally, HER2-positive breast cancer cell lines were used to modulate RANK expression and analyze in vitro the contribution of RANK signaling to anti-HER2 resistance and downstream signaling. Results RANK and RANKL proteins are more frequently detected in HER2-positive tumors that have acquired resistance to anti-HER2 therapies than in treatment-naive ones. RANK (but not RANKL) gene expression increased after dual anti-HER2 neoadjuvant therapy in the cohort from the SOLTI-1114 PAMELA trial. Results in HER2-positive breast cancer cell lines recapitulate the clinical observations, with increased RANK expression observed after short-term treatment with the HER2 inhibitor lapatinib or dual anti-HER2 therapy and in lapatinib-resistant cells. After RANKL stimulation, lapatinib-resistant cells show increased NF-κB activation compared to their sensitive counterparts, confirming the enhanced functionality of the RANK pathway in anti-HER2-resistant breast cancer. Overactivation of the RANK signaling pathway enhances ERK and NF-κB signaling and increases lapatinib resistance in different HER2-positive breast cancer cell lines, whereas RANK loss sensitizes lapatinib-resistant cells to the drug. Our results indicate that ErbB signaling is required for RANK/RANKL-driven activation of ERK in several HER2-positive cell lines. In contrast, lapatinib is not able to counteract the NF-κB activation elicited after RANKL treatment in RANK-overexpressing cells. Finally, we show that RANK binds to HER2 in breast cancer cells and that enhanced RANK pathway activation alters HER2 phosphorylation status. Conclusions Our data support a physical and functional link between RANK and HER2 signaling in breast cancer and demonstrate that increased RANK signaling may contribute to the development of lapatinib resistance through NF-κB activation. Whether HER2-positive breast cancer patients with tumoral RANK expression might benefit from dual HER2 and RANK inhibition therapy remains to be elucidated.

Effect of afatinib alone and in combination with trastuzumab in HER2-positive breast cancer cell lines.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 632-632 ◽  
Author(s):  
Alexandra Canonici ◽  
Kasper Pedersen ◽  
Brigid Browne ◽  
Martina McDermott ◽  
Naomi Walsh ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Cancer Cell Lines ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

632 Background: Trastuzumab and lapatinib have been shown to significantly improve the prognosis for HER2 positive breast cancer patients. However, resistance is a significant clinical problem. The aim of this study is to assess the activity of afatinib, an irreversible pan-HER tyrosine kinase inhibitor, in HER2 overexpressing breast cancer cell lines, including trastuzumab and/or lapatinib resistant cells. Methods: Using proliferation assays, the effect of afatinib was assessed alone and in combination with trastuzumab in HER2 positive cell lines. The effect of afatinib on HER2, Erk and Akt was determined by immunoblotting. Results: The eight HER2 positive breast cancer cell lines tested, including trastuzumab and/or lapatinib resistant cells, responded to afatinib with IC50values ranging from 5 to 80 nM. The combination of afatinib and trastuzumab was additive in four trastuzumab sensitive cell lines and one model of acquired trastuzumab resistant HER2 positive breast cancer. In the remaining three trastuzumab and/or lapatinib resistant cell lines, combined treatment with trastuzumab and afatinib showed no enhancement compared to afatinib alone. Finally, afatinib decreased the phosphorylation of HER2 and Erk in all cell lines tested. Conclusions: Our results suggest that afatinib has activity in HER2 positive breast cancer, including trastuzumab and/or lapatinib resistant breast cancer. We also demonstrate that afatinib in combination with trastuzumab may be more effective than either agent alone in trastuzumab sensitive breast cancer. [Table: see text]

Radiosensitization of HER2-positive breast cancer cell lines with trastuzumab.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11501-e11501 ◽  
Author(s):  
Senem Demirci Alanyali ◽  
Emir Bozkurt ◽  
Hilmi Alanyali ◽  
Burcak Karaca ◽  
Ruchan Uslu
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Breast Cancer Cell ◽  
Breast Cancer Cells ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

e11501 Background: HER2 is a member of the human epidermal growth factor (EGF) receptor family that is blocked by a monoclonal antibody, Trastuzumab (Herceptin). In daily clinical practice, Trastuzumab is being used concurrently with radiotherapy (RT) in breast cancer patients. Administration of Trastuzumab with RT appear to be safe in regard to cardiac morbidity and mortality in patients with relatively modest follow-up duration (less than 5 years). In this study we aimed to determine the possible interactions between RT and Trastuzumab in HER2 positive breast cancer cell line MDA-MB-453. Methods: MDA-MB-453 cells were treated with increased dose of Trastuzumab (10 – 200 µg/mL, 72 hours) and irradiation (0-8 Gy, 4 Gy/min, 48 hours). XTT (Roche) viability assay was used to measure the cytotoxicity of Trastuzumab, and trypan blue method was used to measure the cytotoxicity of irradiation. The sensitization of MDA-MB-453 cell lines was done by IC50 of Trastuzumab with 24 hours treatment followed by 6 and 8 Gy irradiation. Results: Cytotoxicity was increased in a dose and time dependent manner by Trastuzumab and irradiation treatment in MDA-MB-453 cell lines. IC50 values of Trastuzumab and irradiation were found to be 167 µg/mL and 8 Gy, at 48 hours, respectively.Cells were pretreated with IC25 and IC50 doses of Trastuzumab for 24 hours and then irradiated with 6 and 8 Gy doses. The cell viability at 24 and 48 hours were significantly decreased (p=0.0012) compared to single exposures (Trastuzumab or irradiation), indicating that Trastuzumab sensitizes HER2 positive breast cancer cells to irradiation. Conclusions: This preliminary study showed the sensitization effect of Trastuzumab to irradiation in HER2 positive breast cancer cells. Further studies are warranted for the optimal dosing and normal tissue toxicity of this combination.

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