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Review
. 2015 Jan 16;3(1):42-51.
doi: 10.12998/wjcc.v3.i1.42.

Recent advances in the HER2 targeted therapy of gastric cancer

Tasuku Matsuoka  1 , Masakazu Yashiro  1
Affiliations
Review

Recent advances in the HER2 targeted therapy of gastric cancer

Tasuku Matsuoka et al. World J Clin Cases. .

Abstract

Recent advances in molecular targeted therapies, including targeting human epidermal growth factor receptor 2 (HER2), had a major forward step in the therapy for gastric cancer patients. Application of HER2-targeted therapies, in particular trastuzumab in combination with chemotherapy in metastatic HER2-positive gastric cancers, resulted in improvements in response rates, time to progression and overall survival. Nevertheless, as with breast cancer, many patients with gastric cancer develop resistance to trastuzumab. Several promising therapies are currently being developed in combination with chemotherapy to increase the efficacy and overcome the cancer-resistance. Here we review the current overview of clinical application of agents targeting HER2 in gastric cancer. We also discuss the ongoing trials supporting the use of HER2-targeted agents combined with cytotoxic agents or other monoclonal antibodies.

Keywords: Gastric cancer; Human epidermal growth factor receptor 2; Targeting therapy; Trastuzumab.

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Figures

Figure 1
Figure 1
Human epidermal growth factor receptor 2 signaling pathway and interaction with other pathways. This demonstrates schematic representation of the HER-2 family of receptor and their interaction with downstream signalling, along the pathway which are responsible for a variety of biological processes involving cell cycle control, apoptosis, cellular growth, invasion, and angiogenesis. Examples of classes of drugs and corresponding compounds targeting the HER-2 network are also presented. HER1-4 are transmembrane proteins with associated tyrosine kinases. Heterodimerization result in tyrosine kinase activation with the subsequent signaling cascade, and subsequently activates downstream signals, including members of MAPK and PI3K/Akt/mTOR pathways. Trastuzumab and t-DM1 targtets to the extracellular domain IV of HER2. Anti-cancer activity of pertuzumab is interference with HER-receptor dimerization. Lapatinib, afatinib, and tyrosine kinase inhibitors (TKIs) compete for the binding of ATP in the intracellular domain of the receptors. HSP90 suppresses the NH2-terminal ATP binding site which leads to the degradation of client proteins by the ubiquitin proteasome pathway. HER: Human epidermal growth factor receptor; MAPK: Mitogen-activated protein kinase; MEK: Mitogen-activated protein kinase kinase; ERK: Extracellular signal-regulated kinase; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mammalian target of rapamycin.
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