The antibody trastuzumab is approved for treatment of patients with HER2 (ERBB2)-overexpressing breast cancer. A significant fraction of these tumors are either intrinsically resistant or acquire resistance rendering the drug ineffective. The development of resistance has been attributed to failure of the antibody to inhibit phosphoinositide 3-kinase (PI3K), which is activated by the HER2 network. Herein, we examined the effects of PI3K blockade in trastuzumab-resistant breast cancer cell lines. Treatment with the pan-PI3K inhibitor XL147 and trastuzumab reduced proliferation and pAKT levels, triggering apoptosis of trastuzumab-resistant cells. Compared with XL147 alone, the combination exhibited a superior antitumor effect against trastuzumab-resistant tumor xenografts. Furthermore, treatment with XL147 and trastuzumab reduced the cancer stem-cell (CSC) fraction within trastuzumab-resistant cells both in vitro and in vivo. These effects were associated with FoxO-mediated inhibition of transcription of the antiapoptosis gene survivin (BIRC5) and the CSC-associated cytokine interleukin-8. RNA interference-mediated or pharmacologic inhibition of survivin restored sensitivity to trastuzumab in resistant cells. In a cohort of patients with HER2-overexpressing breast cancer treated with trastuzumab, higher pretreatment tumor levels of survivin RNA correlated with poor response to therapy. Together, our results suggest that survivin blockade is required for therapeutic responses to trastuzumab and that by combining trastuzumab and PI3K inhibitors, CSCs can be reduced within HER2(+) tumors, potentially preventing acquired resistance to anti-HER2 therapy.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3563941PMC
http://dx.doi.org/10.1158/0008-5472.CAN-12-2440DOI Listing

Publication Analysis

Top Keywords

trastuzumab-resistant cells
12
breast cancer
12
pi3k inhibitors
8
xl147 trastuzumab
8
trastuzumab reduced
8
trastuzumab
7
trastuzumab-resistant
5
cells rely
4
rely her2-pi3k-foxo-survivin
4
her2-pi3k-foxo-survivin axis
4

Similar Publications

Background: Up to 23% of breast cancer patients recurred within a decade after trastuzumab treatment. Conversely, one trial found that patients with low HER2 expression and metastatic breast cancer had a positive response to trastuzumab-deruxtecan (T-Dxd). This indicates that relying solely on HER2 as a single diagnostic marker to predict the efficacy of anti-HER2 drugs is insufficient.

View Article and Find Full Text PDF

Breast cancer is the most common cancer among women. Among them, human epidermal growth factor receptor-positive (HER2+) breast cancer is more malignant. Fortunately, many anti-HER2 drugs are currently used in clinical treatments to increase patient survival.

View Article and Find Full Text PDF

HER2 overexpression significantly contributes to the aggressive nature and recurrent patterns observed in various solid tumors, notably gastric cancers. Trastuzumab, HER2-targeting monoclonal antibody drug, has shown considerable clinical success; however, readily emerging drug resistance emphasizes the pressing need for improved interventions in HER2-overexpressing cancers. To address this, we proposed targeting the protein-protein interaction (PPI) between ELF3 and MED23 as an alternative therapeutic approach to trastuzumab.

View Article and Find Full Text PDF

HER2 and αβ integrin are independent predictors of breast cancer survival and metastasis. We identify an αβ/HER2 cross-talk mechanism driving invasion, which is dysregulated in drug-resistant HER2+ breast cancer cells. Proteomic analyses reveal ligand-bound αβ recruits HER2 and a trafficking subnetwork, comprising guanosine triphosphatases RAB5 and RAB7A and the Rab regulator guanine nucleotide dissociation inhibitor 2 (GDI2).

View Article and Find Full Text PDF

Hedgehog Pathway Is a Regulator of Stemness in HER2-Positive Trastuzumab-Resistant Breast Cancer.

Int J Mol Sci

November 2024

Department of Medical Biology, Faculty of Medicine, Recep Tayyip Erdogan University, Rize 53100, Turkey.

Article Synopsis
  • * The study explores how the Hedgehog signalling pathway affects trastuzumab resistance in HER2-positive breast cancer, revealing that resistant cell lines show increased Hedgehog activity and stemness markers.
  • * Treatment with the Hedgehog inhibitor GANT61 combined with trastuzumab significantly lowers stemness marker expression, indicating that targeting Hedgehog signalling could help overcome resistance and improve treatment outcomes.
View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!