Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network

@article{Ritter2007HumanBC,
  title={Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network},
  author={Christoph A. Ritter and Marianela P{\'e}rez-Torres and Cammie Rinehart and Marta Garc{\'i}a Guix and Teresa C. Dugger and Jeffrey A. Engelman and Carlos L. Arteaga},
  journal={Clinical Cancer Research},
  year={2007},
  volume={13},
  pages={4909 - 4919}
}
Purpose: We have investigated mechanisms of acquired resistance to the HER2 antibody trastuzumab in BT-474 human breast cancer cells. Experimental Design: BT-474 xenografts established in athymic nude mice were eliminated by trastuzumab. Continuous cell lines (HR for Herceptin resistant) were generated from tumors that recurred in the presence of continuous antibody therapy. Results: The isolated cells behaved resistant to trastuzumab in culture as well as when reinjected into nude mice. They… 
View on AACR
clincancerres.aacrjournals.org
488 Citations
Highly Influential Citations
11
Background Citations
71
Methods Citations
7
Results Citations
3

488 Citations

Citation Type

Citation Type

Cancer Therapy : Preclinical Human Breast Cancer Cells Harboring a Gatekeeper T 798 M Mutation in HER 2 Overexpress EGFR Ligands and Are Sensitive to Dual Inhibition of EGFR and HER 2
TLDR
Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene–amplified breast cancer cells harboring T798Mmutant alleles.
EGFR over-expression and activation in high HER2, ER negative breast cancer cell line induces trastuzumab resistance
TLDR
It is concluded that EGFR over-expression can mediate trastuzumab resistance in both ER positive and ER negative cells and hypothesize that a threshold level of EGFR, in the absence of autocrine ligand production, is required to induce the resistant phenotype.
Human Breast Cancer Cells Harboring a Gatekeeper T798M Mutation in HER2 Overexpress EGFR Ligands and Are Sensitive to Dual Inhibition of EGFR and HER2
TLDR
Simultaneous blockade of HER2 and EGFR should be an effective treatment strategy against HER2 gene–amplified breast cancer cells harboring T798M mutant alleles.
An ERBB1-3 Neutralizing Antibody Mixture With High Activity Against Drug-Resistant HER2+ Breast Cancers With ERBB Ligand Overexpression
TLDR
The data suggest that upregulation of a NRG1-HER3 axis can mediate escape from anti-HER2 therapies, and multitargeted antibody mixtures, such as Pan-HER, can simultaneously remove and/or block targeted ERBB receptor and ligands, thus representing an effective approach against drug-sensitive and -resistant HER2+ cancers.
Rac1 contributes to trastuzumab resistance of breast cancer cells: Rac1 as a potential therapeutic target for the treatment of trastuzumab-resistant breast cancer
TLDR
It is shown that when parental SKBR3 cells become resistant to trastuzumab, Rac1 activity is increased, leading to altered cell morphology, which is accompanied by significant cytoskeleton disorganization, and NSC23766 restores trastzumab-mediated endocytic down-regulation of ErbB2 and reduces extracellular signal-regulated kinase activity in resistant SK BR3 cells.
Different mechanisms for resistance to trastuzumab versus lapatinib in HER2- positive breast cancers -- role of estrogen receptor and HER2 reactivation
TLDR
Combined L + T treatment provides a more complete and stable inhibition of the HER network, and ER functions as a key escape/survival pathway in ER-positive/HER2-positive cells.
Potent anti-proliferative effects of metformin on trastuzumab-resistant breast cancer cells via inhibition of erbB2/IGF-1 receptor interactions
TLDR
The hypothesis that metformin may be more effective against trastuzumab-resistant erbB2-overexpressing breast cancer cells because it targets the critical signaling pathways that are altered with resistance is hypothesized.
Synergistic interaction between trastuzumab and EGFR/HER-2 tyrosine kinase inhibitors in HER-2 positive breast cancer cells
TLDR
Dual targeting of EGFR and Her-2, by combining trastuzumab with EGFR/HER-2 tyrosine kinase inhibitors, may improve response in HER-2 overexpressing breast cancer cells that also express EGFR.
HER-Family Ligands Promote Acquired Resistance to Trastuzumab in Gastric Cancer
TLDR
It is proposed that trastuzumab resistance in gastric cancer is mediated by HER-family ligand upregulation that allows a compensatory activation of HER receptors and maintains downstream signaling activation despite trastzumab therapy.
Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells.
TLDR
Remarkably, Her2-overexpressing breast cancer cells rapidly up-regulate Met expression after trastuzumab treatment, promoting their own resistance, and this study suggests that a subset of Her2 (+) patients may benefit from combined inhibition of her2 and Met.
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 93 REFERENCES
Epidermal growth factor receptor coexpression modulates susceptibility to Herceptin in HER2/neu overexpressing breast cancer cells via specific erbB-receptor interaction and activation.
Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo.
TLDR
The data imply that EGFR tyrosine kinase inhibitors will be effective against HER2-overexpressing breast tumor cells that also express EGFR and support their use in combination with HER2 antibodies, such as Herceptin, against mammary carcinomas with high levels of the HER2 proto-oncogene.
The efficacy of ErbB receptor-targeted anticancer therapeutics is influenced by the availability of epidermal growth factor-related peptides.
TLDR
The degree of ligand-induced rescue from the inhibitors correlated with the potency of ErbB receptor activation and stimulation of the PI3K and MAPK intracellular signaling pathways, suggesting that the efficacy of anticancer drugs that block a single Erb B receptor may be compromised by the presence of exogenous epidermal growth factor-related ligands.
Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells.
TLDR
It is shown that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells, suggesting that the IGF-IR/HER-2 heterodimer contributes to trastzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastudumab.
Trastuzumab (herceptin), a humanized anti-Her2 receptor monoclonal antibody, inhibits basal and activated Her2 ectodomain cleavage in breast cancer cells.
TLDR
It is proposed that the inhibition of HER2 cleavage and prevention of the production of an active truncated HER2 fragment represent a novel mechanism of action of trastuzumab.
Activity of the dual kinase inhibitor lapatinib (GW572016) against HER-2-overexpressing and trastuzumab-treated breast cancer cells.
TLDR
It is reported that concentration-dependent antiproliferative effects of lapatinib were seen in all breast cancer cell lines tested but varied significantly between individual cell lines with up to 1,000-fold difference in the IC(50)s (range, 0.010-18.6 micromol/L).
HER2 kinase domain mutation results in constitutive phosphorylation and activation of HER2 and EGFR and resistance to EGFR tyrosine kinase inhibitors.
TGFα expression impairs Trastuzumab-induced HER2 downregulation
TLDR
The results suggest that unresponsiveness to Trastuzumab may not be due to intrinsic defects in the machinery responsible for HER2 downregulation, but can be associated with a TGFα-related mechanism of escape to HER1 downregulation.
Insulin-like growth factor-I receptor signaling and resistance to trastuzumab (Herceptin).
TLDR
In breast cancer cell models that overexpress HER2/neu, an increased level of IGF-IR signaling appears to interfere with the action of trastuzumab, and strategies that target IGF- IR signaling may prevent or delay development of resistance to trastzumab.
Blockade of the epidermal growth factor receptor tyrosine kinase suppresses tumorigenesis in MMTV y Neu 1 MMTV y TGF-a bigenic mice
TLDR
It is reported that blockade of the epidermal growth factor receptor (EGFR) kinase with AG-1478 markedly delays breast tumor formation in mouse mammary tumor virus (MMTV)yNeu 1 MMTVytransforming growth factor a bigenic mice and increased signaling by ErbB receptors up-regulates MAPK activity, which phosphorylates and destabilizes p27, thus contributing to dysregulated cell cycle progression.
...
1
2
3
4
5
...