Modular anti‐EGFR and anti‐Her2 targeting of SK‐BR‐3 and BT474 breast cancer cell lines in the presence of ErbB receptor‐specific growth factors

Abstract

Over the last decade, a number of monoclonal antibodies and small molecule inhibitors emerged as potent therapeutic agents in the treatment of Her2/neu overexpressing breast cancer. Numerous patients, however, do not adequately respond to anti-epidermal growth factor receptor (EGFR)/Her2 receptor targeting. Receptor-and, in turn, growth-stimulating effects, which potentially hamper antiproliferative cell treatment, have barely been investigated. BT474 and SK-BR-3 breast cancer cell lines were treated with Trastuzumab, Pertuzumab, and Lapatinib alone using different combinations and concentrations. Moreover, epidermal growth factor (EGF) or heregulin (HRG) was added to reveal potential growth factor-mediated compensatory effects. Receptor and intracellular signaling were analyzed as a function of cell treatment. Read-out parameters were cell proliferation and apoptosis. BT474 cells were efficiently driven into quiescence by Trastuzumab, but not by Pertuzumab treatment. Simultaneous EGF or HRG administration, however, restored the BT474 cell proliferation capacity. In contrast, neither therapeutic antibody treatment caused a profound inhibition of SK-BR-3 cell-cycle progress. Lapatinib turned out to be the most potent cell-cycle inhibitor in both cell lines even though its impact was significantly abrogated in the presence of EGF and HRG. The compensatory effect of EGF on Lapatinib-induced cell-cycle inhibition was reversed by Trastuzumab as well as by Pertuzumab treatment. Most importantly, HRGcaused compensation of Lapatinib-induced cell-cycle exit was reversed by Pertuzumab but not by Trastuzumab. Apparently, multiple anti-EGFR/Her2 targeting by using Trastuzumab, Pertuzumab, and Lapatinib more efficiently affects receptor function (interaction and activation) and consequently enhances their antiproliferative capacity. Growth inhibition by anticancer drugs targeted to Her/ErbB receptors, however, can be significantly undermined in the presence of EGF and in particular by HRG treatment, which suggests that specific therapeutic growth factor sequestration might further enhance anti-EGFR/Her2 targeting. '

Sensitization of HER2 Positive Breast Cancer Cells to Lapatinib Using Plants-Derived Isothiocyanates

“…By contrast, in HL60 human myeloid leukemia cells ERN was more effective (IC 50 D 1.9 mM) than SFN (IC 50 D 5.1 mM) (37). In case of lapatinib, our results confirmed previous data showing that BT-474 cells are more sensitive to this drug than SKBR-3 cells (38,39).…”

IL-15 enhances the anti-tumor activity of trastuzumab against breast cancer cells but causes fatal side effects in humanized tumor mice (HTM)

“…In contrast, SK-BR-3-bearing mice were mostly trastuzumab insensitive which is in line with the response characteristic of SK-BR-3 cells in-vitro [28]. Apparently, the immune system enhanced the trastuzumab treatment efficiency in BT474 HTM.…”

The prognostic value of Her4 receptor isoform expression in triple-negative and Her2 positive breast cancer patients

“…The ever-growing body of evidence supporting the favorable impact of Her4 expression in breast cancer suggests the need to reexamine the commonly accepted idea that (over-)expression of (receptor) tyrosine kinases is necessarily associated with oncogenic activity. Only further extensive functional in-vitro and in-vivo analyses focusing on the importance of Her4 in the context of differential Her receptor co-expression will facilitate the consideration of this important receptor in individually optimized therapy based on a modular approach [35]. …”