Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment

Michael Hubalek; Christine Brunner; Karin Matthä; Christian Marth

doi:10.1007/s10354-010-0838-6

Resistance to HER2-targeted therapy: mechanisms of trastuzumab resistance and possible strategies to overcome unresponsiveness to treatment

Wien Med Wochenschr. 2010 Nov;160(19-20):506-12. doi: 10.1007/s10354-010-0838-6. Epub 2010 Oct 26.

Authors

Michael Hubalek¹, Christine Brunner, Karin Matthä, Christian Marth

Affiliation

¹ Department of Gynecology and Obstetrics, Medical University of Innsbruck, Innsbruck, Austria. michael.hubalek@i-med.ac.at

PMID: 20972709
DOI: 10.1007/s10354-010-0838-6

Abstract

Trastuzumab has shown significant efficacy in HER2-overexpressing breast cancers and is approved for patients whose tumors carry this abnormality, both in the metastatic and in the adjuvant settings. However, several issues about its optimal use remain unresolved. Many breast cancer patients with HER2 overexpression do not respond to initial therapy with trastuzumab (Herceptin(®)), and a vast majority of these develop resistance to this monoclonal antibody within one year. This review discusses the molecular mechanisms leading to the development of trastuzumab resistance, including circulating HER2 extracellular domain, loss of PTEN, activation of alternative pathways (e.g. IGFR), and receptor-antibody interaction block. Additionally, the possibility of exploring these aberrations as therapeutic targets that potentially overcome resistance to trastuzumab is highlighted.

Publication types

Review

MeSH terms

Antibodies, Monoclonal / administration & dosage*
Antibodies, Monoclonal / adverse effects
Antibodies, Monoclonal, Humanized
Antineoplastic Agents / administration & dosage*
Antineoplastic Agents / adverse effects
Apoptosis / drug effects
Apoptosis / genetics
Breast Neoplasms / drug therapy*
Breast Neoplasms / genetics*
Cell Division / drug effects
Cell Division / genetics
Drug Delivery Systems*
Drug Resistance, Neoplasm / genetics*
Female
Gefitinib
Gene Expression Regulation, Neoplastic / drug effects
Gene Expression Regulation, Neoplastic / genetics
Humans
Lapatinib
PTEN Phosphohydrolase / genetics
Phosphatidylinositol 3-Kinase / genetics
Prognosis
Quinazolines / administration & dosage
Quinazolines / adverse effects
Receptor, ErbB-2 / genetics*
Signal Transduction / drug effects
Signal Transduction / genetics
Trastuzumab

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Antineoplastic Agents
Quinazolines
Lapatinib
Phosphatidylinositol 3-Kinase
ERBB2 protein, human
Receptor, ErbB-2
PTEN Phosphohydrolase
PTEN protein, human
pertuzumab
Trastuzumab
Gefitinib