Review
The role of HER3 in gastric cancer

https://doi.org/10.1016/j.biopha.2014.08.011Get rights and content

Abstract

Gastric cancer is the second leading cause of cancer mortality in the world. HER family tyrosine kinases play a critical role in the development of gastric cancer. The HER family of receptor tyrosine kinases includes EGF receptor (EGFR), HER2, HER3, and HER4. Targeted drugs antineoplastic therapies such as EGFR tyrosine kinase inhibitors have application with confrontation of gastric cancer. However, less attention has been paid to the oncogenic functions of HER3 essepecially in the gastric cancer due to its lack of intrinsic kinase activity. Recent work, however, has placed the role of HER3 in gastric cancer in the spotlight as a key signaling hub in several contexts. First, HER3 overexpression may be associated with poor prognosis and unfavorable survival mediated by PI3K/AKT signaling pathway. Second, a large amount of direct evidence has emerged the benefit of anti-HER3 agents in combination with EGFR tyrosine kinase inhibitors as well as anti-HER2 agents in gastric cancer. Furthermore, we can further elucidate the relationship between HER3 and MET inhibitors in gastric cancer that the development of resistance to MET inhibitors may result from the overexpression of HER3. This review focuses on the current achievements of the relationship between HER3 and gastric cancer in vivo and in vitro, the development of HER3 molecule-targeted therapy, additionally, the challenge which we will meet in the future.

Introduction

Gastric cancer is the second leading cause of cancer-related mortality worldwide and is the fourth most commonly diagnosed [1]. Although the incidence of gastric cancer has slightly declined in recent decades, there are still 56% of new cases in Eastern Asia, 41% in China, 11% in Japan estimating at 934,000 cases [2].

Most gastric cancer patients present at advanced stage or metastatic disease, however, based on current evidences, overall 5-year survival rates are approximately 30% [3] in the USA and are less than 45% for stage III gastric cancer, even in Japan [4], with median overall survival (OS) and median progression-free survival (PFS) being only 9–13 and 6–7 months [5], respectively, even with the implementation of chemotherapy for the patients with recurrent after surgery therapeutic regimens or the advanced stage disease.

Moreover, with the rapidly development of clinical therapy, traditional chemotherapy agents, which have a predominant effect on proliferating cells, lack an effective chemotherapeutic window, as they are unable to distinguish between rapidly normal cells and tumor cells [6]. With continuous research on gastric cancer molecular biology, molecular-targeted drugs appeared not only improve the efficacy of chemotherapy but also decrease the side effects of drugs, so that the treatment of advanced gastric cancer has entered a new era [7]. Targeted drugs antineoplastic therapies, such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been application with confrontation of gastric cancer. EGFR family tyrosine kinases play a critical role in the development of gastric cancer [8]. Here, we attempt to summarize one of the EGFR family members, HER3, which has not clearly elaboration in gastric cancer.

Section snippets

Her3

There are four members in the HER family, HER1 (EGFR), HER2, HER3 and HER4, which share a common structure of an extracellular ligand-binding domain, a transmembrane domain and an intracytoplasmic tyrosine kinase domain [9], [10]. EGFR is a tyrosine kinase, which is evolutionarily ancient and widely expressed. What is more, additional three members ERBBs2-4, are highly homologous to EGFR and have all been observed in all kinds types of cancer cells [11]. The formation of homodimer or

The HER3 expression and gastric cancer

A functional crosstalk between HER3 and gastric carcinoma has been somewhat elusive until recently. As several studies reported, evidences have begun to emerge on the acquisition of HER3 overexpression, which is a predictor of prognosis. Hayashi et al. studied a total of 134 patients with primary gastric adenocarcinomas who underwent a surgical therapy. They reported that HER3 was highly overexpressed (59%, 79/116) in gastric cancer, and HER3 overexpression was significantly relevant with poor

Conclusion

HER3, as a mirror to the importance of HER2 in tumorigenesis of gastric cancers, has gained more and more attention. However, the prognostic value of HER3 in gastric cancer is controversial, consensus guidelines should be standardized. It will be another novel molecule for investigating the pathogenesis of gastric cancer and a new potent candidate for molecule-target therapy. In addition, HER3 combination with either HER2-targeted or MET inhibitor for resistance and response prediction may be

Disclosure of interest

The authors declare that they have no conflicts of interest concernig this article.

Acknowledgements

This work was partially supported by the Young Scientists Fund of the National Natural Science Foundation of China (81101798) and the Young Scientists Fund of the Natural Science Foundation of Hei Long Jiang Province, China (QC2010115). We are grateful to Tao Liu and Jun Wei Qin for carefully reading and significant suggestions on this manuscript.

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