Treatment of Human Epidermal Growth Factor Receptor 2-Overexpressing Breast Cancer Xenografts With Multiagent HER-Targeted Therapy

Abstract

Combined treatment with gefitinib, trastuzumab, and pertuzumab to block signals from all HER homo- and heterodimers inhibited growth of HER2-overexpressing xenografts statistically significantly better than single agents and dual combinations.

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

“…An ability to switch between ERa and ErbB2 signaling has recently been observed in our tamoxifen resistant cell line MCF-7/TAM R -1 when grown in presence and absence of tamoxifen [15]. This is in line with xenograft models of tamoxifen resistance [46] and letrozole resistance [52], where ErbB blockade restored the antagonistic properties of the endocrine therapy, resulting in better effect of continued endocrine therapy with ErbB blockade than of ErbB blockade alone [52]. Also, ErbB2 overexpressing breast cancer cells with acquired resistance to ErbB directed therapy with lapatinib has been shown to switch from ErbB to ERa signaling for cell survival and growth [53].…”

“…It is becoming increasingly clear that the ErbB system of receptors is tightly coupled, pointing to the importance of dealing with these receptors as a complex network, which should be targeted in combination, rather than as individual receptors [45]. A superior effect of targeting more than one ErbB receptor has also been shown in a breast cancer xenograft model, where a combination of pertuzumab, trastuzumab, and gefitinib more efficiently blocked tumor growth than either single agent [46]. Our resistant cell lines show increased expression of the ErbB3/ 4 ligand heregulin-2b and increased activity of ErbB3 [11] and this increased ErbB3 signaling may in part explain the insensitivity to EGFR/ErbB2 antibody-based treatment as has previously been indicated in both clinical and preclinical studies [47,48].…”

The HOXB7 protein renders breast cancer cells resistant to tamoxifen through activation of the EGFR pathway

“…It is difficult to envision that the current target-specific (usually one target, one molecule) anticancer therapeutics will efficiently eradicate heterogeneous populations of cells, typical of breast cancer. Thus, in a preclinical breast cancer model, a combination treatment that simultaneously blocks multiple signals would be significantly better than single agents or dual combinations (26). Our data implicated HOXB7 as a unique target acting upstream of important RTKs and cognate ligands, whose functional antagonism might allow the attack of multiple therapeutic targets simultaneously in breast cancer.…”

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

“…Although a number of clinical studies support these observations (Gutierrez et al, 2005;Dowsett et al, 2006;Arpino et al, 2007) the molecular mechanisms underlying these phenotypes remain unclear and as a consequence, effective approaches for preventing and overcoming resistance are not yet available (Johnston, 2009).…”