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Stemming Resistance to HER-2 Targeted Therapy

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Abstract

Although the development of trastuzumab and lapatinib has improved the outlook for women with HER-2 positive breast cancer, resistance to HER-2 targeted therapy is a growing clinical dilemma. Recent evidence indicates that the HER-2 pathway may play an important role in the maintenance of cancer stem cells (CSCs). The success of HER-2 targeted therapies may, in part, be explained by their direct activity against HER-2 positive CSCs. Our understanding of the mechanisms involved in resistance to trastuzumab, including loss or blockade of the trastuzumab binding site, activation of alternative signaling pathways, and induction of epithelial–mesenchymal transition (EMT), suggests that CSCs may be at the root of resistance of HER-2 targeted therapy. A variety of novel HER-2 targeted approaches have demonstrated promising preliminary clinical activity. Future clinical trials should involve the integration of technologies to assess the impact of novel HER-2 targeted therapies on HER-2 positive CSCs.

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Abbreviations

ADCC:

antibody dependent cellular cytotoxicity

ALDH1:

aldehyde dehydrogenase 1

ALTTO:

adjuvant lapatinib and/or trastuzumab treatment optimisation

c-Met:

mesenchymal-epithelial transition factor

CSC:

cancer stem cell

CXCR4:

CXC chemokine receptor 4

DCIS:

ductal carcinoma in situ

ECD:

extracellular domain

EGFR:

epidermal growth factor receptor

EMT:

epithelial-mesenchymal transition

ER:

estrogen receptor

Fc:

fragment C

FDA:

Food and Drug Administration

HER-2:

human epidermal growth factor receptor 2

HSP:

heat shock protein

IGF-1R:

insulin-like growth factor-1 receptor

MAPK:

mitogen-activated protein kinase

MFE:

mammosphere formation efficiency

mTOR:

mammalian target of rapamycin

PCDGF:

PC-cell derived growth factor

PI3K:

phosphoinositide 3-kinase

PP2A:

Protein phosphatase 2

PTEN:

phosphatase and tensin homolog

RT-PCR:

reverse transcriptase polymerase chain reaction

siRNA:

small interfering ribonucleic acid

VEGF:

vascular endothelial growth factor

VEGFR:

vascular endothelial growth factor receptor

XIAP:

X-linked inhibitor of apoptosis protein

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Authors and Affiliations

  1. Department of Medical Oncology, Jules Bordet Institute, Brussels, Belgium

    Philippe L. Bedard, Fatima Cardoso & Martine J. Piccart-Gebhart

  2. Université Libre de Bruxelles, Brussels, Belgium

    Fatima Cardoso & Martine J. Piccart-Gebhart

  3. Medicine Department, Jules Bordet Institute, Rue Heger-Bordet 1, 1000, Brussels, Belgium

    Martine J. Piccart-Gebhart

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  1. Philippe L. Bedard
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  2. Fatima Cardoso
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  3. Martine J. Piccart-Gebhart
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Correspondence to Martine J. Piccart-Gebhart.

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Bedard, P.L., Cardoso, F. & Piccart-Gebhart, M.J. Stemming Resistance to HER-2 Targeted Therapy. J Mammary Gland Biol Neoplasia 14, 55–66 (2009). https://doi.org/10.1007/s10911-009-9116-x

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