Resistance to Trastuzumab in Breast Cancer
- 14 December 2009
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 15 (24), 7479-7491
- https://doi.org/10.1158/1078-0432.ccr-09-0636
Abstract
HER2 is a transmembrane oncoprotein encoded by the HER2/neu gene and is overexpressed in approximately 20 to 25% of invasive breast cancers. It can be therapeutically targeted by trastuzumab, a humanized IgG1 kappa light chain monoclonal antibody. Although trastuzumab is currently considered one of the most effective treatments in oncology, a significant number of patients with HER2-overexpressing breast cancer do not benefit from it. Understanding the mechanisms of action and resistance to trastuzumab is therefore crucial for the development of new therapeutic strategies. This review discusses proposed trastuzumab mode of action as well as proposed mechanisms for resistance. Mechanisms for resistance are grouped into four main categories: (1) obstacles preventing trastuzumab binding to HER2; (2) upregulation of HER2 downstream signaling pathways; (3) signaling through alternate pathways; and (4) failure to trigger an immune-mediated mechanism to destroy tumor cells. These potential mechanisms through which trastuzumab resistance may arise have been used as a guide to develop drugs, presently in clinical trials, to overcome resistance. The mechanisms conferring trastuzumab resistance, when completely understood, will provide insight on how best to treat HER2-overexpressing breast cancer. The understanding of each mechanism of resistance is therefore critical for the educated development of strategies to overcome it, as well as for the development of tools that would allow definitive and efficient patient selection for each therapy. (Clin Cancer Res 2009;15(24):7479–91)Keywords
This publication has 132 references indexed in Scilit:
- Targeting the phosphoinositide 3-kinase pathway in cancerNature Reviews Drug Discovery, 2009
- Novel anticancer targets: revisiting ERBB2 and discovering ERBB3Nature Reviews Cancer, 2009
- Ligand-Independent HER2/HER3/PI3K Complex Is Disrupted by Trastuzumab and Is Effectively Inhibited by the PI3K Inhibitor GDC-0941Cancer Cell, 2009
- Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicityOncogene, 2008
- EGF–ERBB signalling: towards the systems levelNature Reviews Molecular Cell Biology, 2006
- Exploiting the PI3K/AKT Pathway for Cancer Drug DiscoveryNature Reviews Drug Discovery, 2005
- ERBB receptors and cancer: the complexity of targeted inhibitorsNature Reviews Cancer, 2005
- Structural basis for inhibition of the epidermal growth factor receptor by cetuximabCancer Cell, 2005
- PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patientsCancer Cell, 2004
- Structure of the extracellular region of HER2 alone and in complex with the Herceptin FabNature, 2003