scholarly journals A preclinical evaluation of the MEK inhibitor refametinib in HER2-positive breast cancer cell lines including those with acquired resistance to trastuzumab or lapatinib

Oncotarget ◽  
2017 ◽  
Vol 8 (49) ◽  
pp. 85120-85135 ◽  
Author(s):  
John O’Shea ◽  
Mattia Cremona ◽  
Clare Morgan ◽  
Malgorzata Milewska ◽  
Frankie Holmes ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Preclinical Evaluation ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

scholarly journals The Novel Oral mTORC1/2 Inhibitor TAK-228 Reverses Trastuzumab Resistance in HER2-Positive Breast Cancer Models

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2778
Author(s):  
Marta Sanz-Álvarez ◽  
Ester Martín-Aparicio ◽  
Melani Luque ◽  
Sandra Zazo ◽  
Javier Martínez-Useros ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Breast Cancer Cell ◽  
Acquired Resistance ◽  
Mtor Inhibitors ◽  
Breast Cancer Cell Lines ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Positive Breast Cancer Cell ◽  
Positive Breast Cancer

The use of anti-HER2 therapies has significantly improved clinical outcome in patients with HER2-positive breast cancer, yet a substantial proportion of patients acquire resistance after a period of treatment. The PI3K/AKT/mTOR pathway is a good target for drug development, due to its involvement in HER2-mediated signalling and in the emergence of resistance to anti-HER2 therapies, such as trastuzumab. This study evaluates the activity of three different PI3K/AKT/mTOR inhibitors, i.e., BEZ235, everolimus and TAK-228 in vitro, in a panel of HER2-positive breast cancer cell lines with primary and acquired resistance to trastuzumab. We assess the antiproliferative effect and PI3K/AKT/mTOR inhibitory capability of BEZ235, everolimus and TAK-228 alone, and in combination with trastuzumab. Dual blockade with trastuzumab and TAK-228 was superior in reversing the acquired resistance in all the cell lines. Subsequently, we analyse the effects of TAK-228 in combination with trastuzumab on the cell cycle and found a significant increase in G0/G1 arrest in most cell lines. Likewise, the combination of both drugs induced a significant increase in apoptosis. Collectively, these experiments support the combination of trastuzumab with PI3K/AKT/mTOR inhibitors as a potential strategy for inhibiting the proliferation of HER2-positive breast cancer cell lines that show resistance to trastuzumab.

scholarly journals Erratum to: Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours

2014 ◽  
Vol 148 (3) ◽  
pp. 697-697
Author(s):  
Brigid C. Browne ◽  
Alex J. Eustace ◽  
Susan Kennedy ◽  
Neil A. O’Brien ◽  
Kasper Pedersen ◽  
...  
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

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.

Sign in / Sign up

Export Citation Format

Share Document