Targeting the function of the HER2 oncogene in human cancer therapeutics
Open Access
- 7 May 2007
- journal article
- review article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 26 (46), 6577-6592
- https://doi.org/10.1038/sj.onc.1210478
Abstract
The year 2007 marks exactly two decades since human epidermal growth factor receptor-2 (HER2) was functionally implicated in the pathogenesis of human breast cancer (Slamon et al., 1987). This finding established the HER2 oncogene hypothesis for the development of some human cancers. An abundance of experimental evidence compiled over the past two decades now solidly supports the HER2 oncogene hypothesis. A direct consequence of this hypothesis was the promise that inhibitors of oncogenic HER2 would be highly effective treatments for HER2-driven cancers. This treatment hypothesis has led to the development and widespread use of anti-HER2 antibodies (trastuzumab) in clinical management resulting in significantly improved clinical antitumor efficacies that have transformed the clinical practice of oncology. In the shadows of this irrefutable clinical success, scientific studies have not yet been able to mechanistically validate that trastuzumab inhibits oncogenic HER2 function and it remains possible that the current clinical advances are a consequence of the oncogene hypothesis, but not a translation of it. These looming scientific uncertainties suggest that the full promise of the treatment hypothesis may not yet have been realized. The coming decade will see a second generation of HER2-targeting agents brought into clinical testing and a renewed attempt to treat HER2-driven cancers through the inactivation of HER2. Here, I review the development of treatments that target HER2 in the context of the HER2 oncogene hypothesis, and where we stand with regards to the clinical translation of the HER2 oncogene hypothesis.This publication has 143 references indexed in Scilit:
- The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesisOncogene, 2007
- Escape from HER-family tyrosine kinase inhibitor therapy by the kinase-inactive HER3Nature, 2007
- A system for quantifying dynamic protein interactions defines a role for Herceptin in modulating ErbB2 interactionsProceedings of the National Academy of Sciences of the United States of America, 2006
- Molecular basis for sensitivity and acquired resistance to gefitinib in HER2-overexpressing human gastric cancer cell lines derived from liver metastasisBritish Journal of Cancer, 2006
- HER2 expression as a potential marker for response to therapy targeted to the EGFRBritish Journal of Cancer, 2006
- Trastuzumab after Adjuvant Chemotherapy in HER2-Positive Breast CancerThe New England Journal of Medicine, 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
- Drug-induced ubiquitylation and degradation of ErbB receptor tyrosine kinases: implications for cancer therapyThe EMBO Journal, 2002
- Human Breast Cancer: Correlation of Relapse and Survival with Amplification of the HER-2/ neu OncogeneScience, 1987