Stemming Resistance to HER-2 Targeted Therapy

  • Philippe L. Bedard
  • Fatima Cardoso
  • Martine J. Piccart-Gebhart
Article

DOI: 10.1007/s10911-009-9116-x

Cite this article as:
Bedard, P.L., Cardoso, F. & Piccart-Gebhart, M.J. J Mammary Gland Biol Neoplasia (2009) 14: 55. doi:10.1007/s10911-009-9116-x

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.

Keywords

Breast neoplasmserbB-2 receptorMonoclonal antibodiesProtein-tyrosine kinasesCancer stem cells

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

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Philippe L. Bedard
    • 1
  • Fatima Cardoso
    • 1
    • 2
  • Martine J. Piccart-Gebhart
    • 1
    • 2
    • 3
  1. 1.Department of Medical OncologyJules Bordet InstituteBrusselsBelgium
  2. 2.Université Libre de BruxellesBrusselsBelgium
  3. 3.Medicine DepartmentJules Bordet InstituteBrusselsBelgium