Elsevier

Journal of Controlled Release

Volume 146, Issue 3, 15 September 2010, Pages 264-275
Journal of Controlled Release

Review
The role of HER2 in cancer therapy and targeted drug delivery

https://doi.org/10.1016/j.jconrel.2010.04.009Get rights and content

Abstract

HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer, and gastric cancer. Since the discovery of its role in tumorigenesis, HER2 has received great attention in cancer research during the past two decades. Successful development of the humanized monoclonal anti-HER2 antibody (Trastuzumab) for the treatment of breast cancer further spurred scientists to develop various HER2 specific antibodies, dimerization inhibitors and kinase inhibitors for cancer therapy. On the other hand, the high expression of HER2 and the accessibility of its extracellular domain make HER2 an ideal target for the targeted delivery of anti-tumor drugs as well as imaging agents. Although there is no natural ligand for HER2, artificial ligands targeting HER2 have been developed and applied in various targeted drug delivery systems. The emphasis of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. The structure and signal pathway of HER2 will be briefly described. The role of HER2 in tumorigenesis and its relationship with other tumor markers will be discussed. For the HER2 targeted cancer therapy, numerous strategies including the blockage of receptor dimerization, inhibition of the tyrosine kinase activity, and interruption of the downstream signal pathway will be summarized. For the targeted drug delivery to HER2 positive tumor cells, various targeting ligands and their delivery systems will be described in details.

Introduction

Human Epidermal Growth Factor Receptor 2 (HER2), also known as ErbB2, c-erbB2 or HER2/neu, is a 185 kDa protein (p185) with an intracellular tyrosine kinase domain and an extracellular ligand binding domain. In humans, HER family includes four structurally related members, HER1 (ErbB1, also known as EGFR), HER2 (ErbB2), HER3 (ErbB3) and HER4 (ErbB4). Although HER2 is the only receptor which has no identified ligand, it is the preferred partner to form heterodimer with other HER members. HER2 involved heterodimerization is the most potent signal transduction pathway among all dimmers formed by the HER family [1]. HER2 plays important roles in cell growth, survival, and differentiation in a complex manner. The major signaling pathways mediated by HER2 involve mitogen-activated protein kinase (MAPK) pathway and phosphatidylinositol 3-kinase (PI3K) pathway. As a key gene for cell survival, HER2 gene amplification and protein overexpression lead to malignant transformation [2]. It directly associates with poor clinical outcomes in breast, ovarian, gastric, prostate and other cancers.

The successful development of trastuzumab (HerceptinTM), an anti-HER2 antibody, has had a major impact on the treatment of breast cancer [3]. Since then, a variety of HER2 specific antibodies and small molecular inhibitors have been assessed in clinical trials [4]. Both HER2 receptor and the whole HER2 signaling pathway have been extensively studied as the target for cancer therapy. Both the upstream and downstream of the HER2 signaling pathway are promising targets to block the signal and inhibit the tumor growth. Moreover, as an overexpressed cyto-membrane protein, HER2 is an attractive marker for targeted drug delivery to tumor cells.

The aim of this review is to elucidate the roles of HER2 in cancer therapy and targeted drug delivery. Various therapeutic strategies targeting HER2, as well as targeted drug delivery systems will be discussed.

Section snippets

HER2 structure

Similar to all HER receptors, HER2 is a type 1 transmembrane glycoprotein composed of three distinct regions: an N-terminal extracellular domain (ECD), a single α-helix transmembrane domain (TM), and an intracellular tyrosine kinase domain.

As the largest part of HER2, the N-terminal ECD contains approximately 600 residues (90–110 kDa) which could be divided into four subdomains (I–IV) (Fig. 1A). Subdomains I and III can form a binding site for the receptor's potential ligands [5]. Whereas the

HER2 as a target for cancer therapy

Almost immediately after the discovery of its role in tumorgenesis, HER2 was targeted for cancer therapy. Since all the three domains of HER2 are responsible for a specific aspect of the signaling pathway, each domain can be targeted separately to block the HER2 signaling. Moreover, HER2 can be directly suppressed by oligonucleotides including antisense oligonucleotide and siRNA. There are several reasons for HER2 receptor to become an important therapeutic target for cancer therapy. First,

Targeted delivery of drugs to HER2 positive tumor cells

HER2 is highly expressed in a significant proportion of breast cancer, ovarian cancer and gastric cancer cases. The overexpression of HER2 is also clearly associated with more aggressive tumor phenotypes and poor prognosis, thus making it an attractive target for cancer therapy. Moreover, the overexpression of HER2 receptor on tumor cells and accessibility of the extracellular domain of HER2 make it an ideal marker for the receptor mediated drug delivery systems [119]. Although there is no

Conclusions

Since the discovery of its important roles in tumorigenesis, HER2 has attracted enormous attention as a target for cancer therapy. The discovery of trastuzumab represents one of the most successful advances in breast cancer therapy in the past two decades. Although trastuzumab benefits a lot of patients with HER2 overexpression, moderate potency, drug resistance and toxic side-effects compromise its therapeutic effect. As a result, many other agents targeting the HER2 signaling pathway, or even

Search strategy

To summarize the most recent advances in HER2 related topics, MEDLINE and CAS databases were searched using Pubmed (National Library of Medicine) and Scifinder (Chemical Abstracts Service). The search included all the papers and conference abstracts published between January 2000 and May 2009. To supplement to the result, several important original papers before Jan. 2000 were also collected, but the total number was less than 10. Search words included HER2, pathway, trastuzumab, herceptin,

Acknowledgements

This work was supported by a Concept Award (W81XWH-08-1-0603) from the Department of Defense Breast Cancer Research Program, a grant (1R21CA143683-01) from the National Cancer Institute at NIH, and a start-up package at the University of Missouri-Kansas City.

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