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The role of HER3 in gastric cancer
Biomedicine & Pharmacotherapy 68 (2014) 809–812
Available online at
ScienceDirect www.sciencedirect.com
Review
The role of HER3 in gastric cancer Liying Wang, Hengheng Yuan, Yanjing Li, Yu Han * Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, PR China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 July 2014 Accepted 6 August 2014
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. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: HER3 Gastric cancer Monoclonal antibody MET inhibitor
1. 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 5year 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,
* Corresponding author. Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, 150 Haping St, Nangang District, Harbin 150081, PR China. Tel.: +86 451 86298268; fax: +86 451 86298689. E-mail address: [email protected] (Y. Han). http://dx.doi.org/10.1016/j.biopha.2014.08.011 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
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. 2. 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 heterodimer owing to binding with corresponding ligands triggers
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a complex signal transduction cascade, predominantly through phosphoinositide-3-kinase (PI3K)/Akt and extracellular signalregulated kinase1/2(ERK), adjusting the proliferation, migration, adhesion, angiogenesis, and apoptosis of cancer cells [12,13]. The HER2 receptor is distinguished with having no bind ligand, however, it preferred heterodimerization partner of the other HER family members, especially heterodimerized with HER3, and the HER2/HER3 heterodimer is likely to be the most effective complex for activating downstream pathways [14,15]. HER3, however, is encoded by the proto-oncogene c-ErbB3, which is a glycoprotein of 180 kDa. The HER3 gene is expressed as a 6.2- and a 1.4-kb transcript. The former encodes the full-length transmembrane protein and the latter unique truncated extracellular fragment is predicted to translate into a protein with 183 amino acids, of which the first 140 amino acids are similar to the Nterminus of HER3 and the 43 carboxy-terminal amino acids [16]. The HER3 full-length receptor has the characteristic extracellular domain structure as the same as the other family members, which consisted of four subdomains called L1 (I), C1 (II), L2 (III), and C2 (IV) [17]. Members of ErbB family interact with various ligands. As its name shows, EGFR has been suggested to interact with EGF as well as other ligands including betacellulin (BTC), epigen (EPG), epiregulin (EPR), transforming growth factor-a (TGF-a), amphiregulin (AR), and hearin-binding EGF-like growth factor (HB-EGF). It is known that HER3 has been found interacting with neuregulin (NRG)-1 and -2. HER3 is distinguished with the other ErbB family members by two points. First, HER3 is the unique one, which lacks a functioning kinase domain [18]. A large number of evidence suggests that even though HER3 is able to bind ATP, the phospho-transfer reaction is impaired catalytically [18]. Second, HER3 plays a crucial role in inducing the PI3K-AKT pathway to bind the PI3K p85 subunit through six consensus phosphotyrosine docking sites on its Cterminal [19,20]. As Osaki et al. proved that HER3 is essential to maintain PI3K/AKT signaling which induces gastric cancer cells proliferation [21]. It seems that HER3 activities as the key link between the receptor tyrosine kinase (RTK) and PI3K activation in RTK-driven tumors, such as gastric, colon, bladder, and non-small cell lung cancers. Li et al. investigated the mechanism through HER3 siRNA both in vitro and in vivo assay. To their surprise, HER3 knockdown is able to inhibit cell migration in vitro and metastasis in vivo by downregulating MMPs, specifically MMP1, MMP2 and MMP9 with regards to inactivation of PI3K/AKT signaling [22]. However, Seshagiri et al. surveyed the identification of HER3 somatic mutations in 11% and 12% of colon and gastric cancers, respectively. Most of the recurrent mutations are within the ECD (with a few located in the kinase domain). However, the mechanism by which ECD mutations activate HER3 is still unclear. Although a series of experiments in vivo and in vitro conclude that the presence of activating HER3 mutations increases the significance of HER3 in cancer [23]. Multiple evidences demonstrated that the transmission of EGFR homodimer signals is respectively weaker, and HER3 homodimer will never transform even in the presence of ligand. A majority of researches have shown that HER3 is the indispensible chaperones for HER2, which could induce tumor cell lines proliferation in breast cancers [24]. Overexpression of HER2 results in the increased formation of heterodimer. Moreover, the signal is examined as the most potent than any other homodimers or heterdimers. Interestingly, multiple studies reveal that as HER2 has no known ligand, and HER3’s intrinsic functions kinase is defective, so, they have been most readily complexes with each other. Within such tumor, the HER2–HER3 dimer has been demonstrated to be the greatest significance for tumor formation and tumor maintenance, furthermore, which is being the most mitogenic and transforming of them all [25–28]. In recent years,
more attentions have been paid to the relationships between HER3 and tumors, especially in breast cancer, ovarian cancer, esophageal cancer, laryngeal cancer, malignant melanoma and squamous cell carcinoma [29]. To our best knowledge, the role of HER3 in gastric cancer is relatively poor.
3. The role of HER3 in gastric cancer 3.1. 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 prognosis and a decreased survival [30]. Similarly, some authors used tissue microarray (TMA) for the reading of immunohistochemical analysis and fluorescence in situ hybridization (FISH), and employed different criteria for the interpretation of EGFR, HER3, HER4 expression. They observed that HER3 expression might have an impact on tumors progression, and HER3 expressed in the nucleus predicted poor survival [31]. Coincidentally, it has been demonstrated that HER3 has a significantly higher amplified rate in gastric cancer compared gastric cancer group with a nontumorous group (13.7% vs 2.0%, P < 0.01). It elucidated that overexpression of HER3 protein is not only involved in the process of gastric tumorigenesis, but also related to TNM stage and low survival rate [32]. In a recent study, Ocana et al. presented a metaanalysis aiming at evaluating the role of HER3 in relation to survival in solid tumors. They identified 12 studies that employed IHC techniques for the assessment of HER3 expression, suggesting that levels of HER3 overexpression in colorectal, gastric, and breast cancer ranging from 20% to 60%. What is more, there was a closer association between HER3 overexpression and detrimental outcome compared with normal HER3 expression, specially, most linked with gastric cancer [33]. Though considerable studies have been conducted to predict the prognostic value of HER3 overexpression of gastric cancer, the detailed mechanism has remained unclear. The latest investigation detected HER3 by means of both real-time PCR and IHC in 161 gastric cancer patients, and assessed its related downstream signaling PI3K/AKT activity and clinical characteristics by statistical analysis. In this study, HER3 knockdown inhibited gastric cancer cell lines proliferation, tumor growth and migration. However, it had no apparently impact on HER2 expression and activity [22]. This finding illustrated that HER3 was becoming an independent factor which predicts unfavorable prognosis and detrimental survival mediated by PI3K/AKT signaling pathway, and more attention should be paid on it as a potent candidate for molecular-targeted therapy in various types of gastric cancer. The prognostic role of HER3, however, has not yet reached a consensus. More recently, Jacome et al. performed a retrospective study including 201 patients with gastric and esophagogastric junction adenocacinoma stages 0–IV (AJCC 6th edition) who underwent primary tumor resection. Weibull distribution was used to analysis multivariate prognostic factors performed by a regression model. To our surprise, they clarified that there was no correlation between cytoplasmic HER3 expression and tumor depth, nodal metastases, or TNM stage. Moreover, the association among membrane HER3 expression, clinicopathological characteristics, and overall survival was not evaluated because of the 200 samples only one patient showed membrane positivity [34]. Some
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authors concluded that HER3 expression has been detected in both the intestinal type [32] and the diffuse type [31], but the association of prognostic in gastric cancer patients is still not intimately. The controversial results may be due to the methods for detecting HER3 expression are various and there is still no consensus about the criteria to be adopted for the reading of HER3 expression in gastric cancer. Overall, large prospective trials with validated methodology are needed to determine the real prognostic value of HER3 expression.
overcome resistance to HER2/MAPK/PI3K axis inhibition. They suggested that HER3 trans-phsphorylation and activation of HER3 dependent survival pathway contributed to the MET overexpression and constitutive activation, and HER3 may play a significant role in the acquisition of resistance to MET inhibition. Therefore, conclusion can be deduced that HER3 knockdown led to a reversion of the resistance to MET inhibitors [8,45].
3.2. HER3 and monoclonal antibody in gastric cancer
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 reliable and introduce a new era of personalized medicine.
It is known that HER3 has been disregarded as a cancer target due to the absence of intrinsic kinase activity in its intracellular domain. Thus, targeting the HER3 ECD through antibodies is becoming the focus. LJM716, a human anti-HER3 monoclonal antibody, is selective for an epitope created by domains II and IV of the HER3 ECD [35], which also inhibits ligand-induced and ligandindependent HER3 dimerization, as a single agent. Garrett et al. examined the effects of LJM716 through a series of experiments recently. In this study, they examined the impacts of LJM716 by different modes of aberrant PI3K pathway activation in cancer cells and xenografts in mice. They found LJM716 reduced HER2-HER3 and HER3-p85 dimers, p-HER3 and p-AKT, and delayed growth of HER2+ xenografts [36]. In this setting, additionally, LJM716 was proposed to significantly improve survival of mice when added to the doublet and synergistically induce cell death when given in combination with BY719, a PI3K inhibitor, which competes with ATP [37]. Furthermore, these data support the idea that a pure HER3 opponent to the disease in which HER3 is well established to mediate the PI3K pathway signal expressing oncoprotein as well as the key node of feedback regulation. More recently, fortunately, a large amount of direct evidence has emerged in a study examining the benefit of anti-HER3 agents in combination with EGFR tyrosine kinase inhibitors as well as anti-HER2 agents. Currently, EGFR and HER2 targeting was succeeded by a feedback upregulation of HER3 [38]. For instance, a preclinical study confirmed that HER3-PI3K axis may play a key role in survival of HER2-dependent cells and the ligand-lack HER2, and kinase-less HER3 may weaken the function of anti-HER2 therapy, what is more, targeting of HER3 and HER2 may act synergistically on the therapeutic value of HER2+ breast and gastric cancer patients [36–38]. Based on the data presented herein, the combination of a HER3 antibody that eliminates both ligand-dependent and -independent HER3 dimerization and an ATP competitive p110a inhibitor (BYL719) will be a strategy for dual blockade of HER2/HER3/PI3K axis [36]. 3.3. HER3 and MET in gastric cancer Recent studies have demonstrated that MET acts as the key in a high percentage of human tumors [39]. Evidences have illustrated that amplification of the MET gene and overexpression of the MET protein were observed in 10-20% of gastric cancer [40–42]. Due to the gene amplification associated with receptor overexpression, MET receptor is frequently constitutively activated. Several studies have shown a crosstalk between MET and HER family members in the context of the acquisition of a biochemical and functional interplay, such as in the MKN-45 gastric cell line [43,44]. Since MET-independent activation of the MAPK or PI3K pathways may drive cells ‘‘addicted’’ to oncogene, so targeting MET has been taken into account in recent studies. However, MET reactivating the pathway above will be critically overlapping with those generated by HER members, which induces the resistance to the targeting agents. Corso et al. investigated the mechanisms, which provided a rationale for the use of MET inhibitors to
4. Conclusion
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. References [1] Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. J Cancer Epidermal Biomarkers Prev 2010;19:1893–907. [2] Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad J Med 2005;81:419–24. [3] Siegel R, Naishadham D, Jemal A. Cancer statistics CA Cancer. J Clin 2013;63:11–30. [4] Nashimoto A, Akazawa K, Isobe Y, Miyashiro I, Katai H, Kodera Y, et al. Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. J Gastric Cancer 2013;16:1–27. [5] Shimoyama S. Unraveling trastuzumab and lapatinib inefficiency in gastric cancer: future steps. J Mol Clin Oncol 2014;2:175–81. [6] Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction a rationale for molecular targeting in cancer therapy. J Nat Clin Pract Oncol 2006;3:448– 57. [7] Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. J Ann Oncol 2008;19:1523–9. [8] Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. J Cancer 2002;94(5):593–1611. [9] Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. J EMBO 2010;19:3159–67. [10] Schlessinger J. Common and distinct elements is cellular signaling via EGF and FGF receptors. J Sci 2004;306:1506–7. [11] Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett J 2012;318:124–34. [12] Yokoyama H, Ikehara Y, Kodera Y, Ikehara S, Yatabe Y, Mochizuki Y, et al. Molecular basis for sensitivity and acquired resistance to gefitinib in HER2 overexpression human gastric cancer cell lines derived from liver metastasis. Br J Cancer 2006;95:1504–13. [13] Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res J 2008;68:9375–83. [14] Lesma E, Grande V, Ancona S, Carelli S, Maria A, Giulio D, et al. Anti-EGFR antibody efficiently and specifically inhibits human TSC2/smooth muscle cell proliferation: possible treatment options for TSC and LAM. PloS One 2008;3:e3558.
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[15] Hirata A, Hosoi F, Miyagawa M, Ueda S, Naito S, Fujii T, et al. HER2 overexpression increases sensitivity to gefitinib, an epidermal growth factor receptor tyrosine kinase inhibitor, through inhibition of HER2/HER3 heterodimer formation in lung cancer cells. Cancer Res J 2005;65:4253–60. [16] Srinivasan R, Leverton KE, Sheldon H, Hurst HC, Sarraf C, Gullick WJ. Intracellular expression of the truncated extracecellular domain of c-erbB3/HER3. Cell Sign J 2001;13:321–30. [17] Sithanandam G, Anderson LM. The ERBB3 receptor in cancer and cancer gene therapy. Cancer Gene Ther J 2008;15:413–48. [18] Jura N, Shan Y, Cao X, Shaw DE, Kuriyan J. Structural analysis of the catalytically inactive kinase domain of the human EGF receptor 3. Proc Natl Acad Sci U S A 2009;106:21608–13. [19] Fedi P, Pierce JH, Fiore PP, Kraus MH. Efficient coupling with phosphatidulinositol 3-kinase, but not phospholipase C gamma or GTPase-acticating protein, distinguishes ErbB3 signaling from that og other ErbB/EGFR family members. Mol Cell Biol J 1994;14:492–500. [20] Soltoff SP, Carraway III KL, Prigent SA, Gullick WG, Cantley LC. ErbB3 is involved in activation of phosphatidulinositol 3-kinase by epidermal growth factor. Mol Cell Biol J 1994;14:3550–8. [21] Osaki M, Oshimura M, Ito H. PI3K-Akt pathway: its functions and alterations in human cancer. J Apoptosis 2004;9:667–76. [22] Wu XY, Chen Y, Li G, Xia L, Gu R, Wen X, et al. HER3 is associated with poor survival of gastric adenocarcinoma: HER3 promotes proliferation, survival and migration of human gastric cancer mediated by PI3K/AKT signaling pathway. Med Oncol J 2014;31:903. [23] Seshagir S, Jaiswal BS, Kljavin NM. Oncogenic-ERBB3 mutations in human cancers. Cancer Cell J 2013;23:603–17. [24] Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer J 2009;9(7):463–75. [25] Vaugh DB, Stanford JC, Young C, Hicks DJ, Wheeler F, Rinehart C, et al. HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res J 2012;72:2672–82. [26] Alimandi M, Romano A, Curia MC, Muraro R, Fedi P, Aaronson SA, et al. Cooperative signaling of ErbB3 and ErbB2 in neoplastic transformation and human mammary carcinomas. Oncogene J 1995;10:1813–21. [27] Lee-Hoeflich ST, Crocker L, Yao E, Pham T, Munroe X, Hoeflich KP, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res J 2008;68:5878–87. [28] Holbro T, Beerli RR, Maurer F, Koziczak M, Barbas CF, Hynes NE. The ErbB2/ErbB3 heterodimer functions as an oncogenic unit: ErbB2 requires ErbB3 to drive breast tumor cell proliferation. Proc Natl Acad Sci U S A 2003;100:8933–8. [29] Cervantes A, Roda D, Tarazona N, Rosello S, Perez-Fidalgo JA. Current status of targeted therapies in advanced gastric cancer. Expert Opin Ther Targets 2012;16:S29–34. [30] Hayashi M, Inokuchi M, Sugihara K, Yamada H, Kojima K, Kumagai J, et al. High expression of HER3 is associated with a decreased survival in gastric cancer. Clin Cancer Res J 2008;14:23.
[31] Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, Costa daWL, et al. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. Clin Oncol J 2011;29(22):3030–6. [32] Zhang XL, Yang YS, Xu DP, Qu J, Guo M, Gong Y, et al. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg 2009;33:2112–8. [33] Ocana A, Vera-Badillo F, Seruga B, Temoleton A, Pandiella A, Amir E. HER3 overexpression and survival in solid tumors: a meta-analysis. Natl Cancer Inst J 2013;105:266–73. [34] Jacome AAA, Wohonrath DR, Neto CR, Carneseca EC, Serrano SV, Viana LS, et al. Prognostic value of epidermal growth factor receptors in gastric cancer: a survival analysis by Weibull model incorporating long-term survivors. Gastric Cancer J 2014;17(1):76–86. [35] Garner AP, Bialucha CU, Sprague ER, Garrett JT, Sheng Q, Li S, et al. An antibody that locks HER3 in the active conformation inhibits tumor growth driven by HER2 or neuregulin. Cancer Res J 2013;73:6042–135. [36] Garrett JT, Sutton CR, Kuruoi R, Bialucha CU, Ettenberg SA, Conllins SD, et al. Combination of antibody that inhibits ligand-independent HER3 dimerization a p110alpha inhibitor potently blocks PI3K signaling and growth of HER2+ breast cancers. Cancer Res J 2013;73:6013–23. [37] Gala K, Chandarlapaty S. Molecular pathways: HER3 targeted therapy. Clin Cancer Res J 2014;20(6):1410–6. [38] Sergina NV, Rausch M, Wang D, Blair J, Hann B, Shokat KM, et al. Escape from HER family tyrosine kinase inhibitor therapy by the kinase-inactive HER3. Nature J 2007;445:437–41. [39] Migliore C, Giordano SS. Molecular cancer therapy: can our expectation be MET? Eur J Cancer 2008;44:641–51. [40] Nakajima M, Sawada H, Yamada Y, Tatsumi M, Yamashita J, Matsuda M, et al. The prognostic significance of amplification and overexpression of c-met and c-erbB2 in human gastric carcinomas. Cancer J 1999;85: 1894–902. [41] Kuniyasu H, Yasui W, Kitadai Y, Yokozaki H, Ito H, Tahara E. Frequent amplification of the c-met gene in scirrhous type stomach cancer. Biophys Res Commun 1992;189:227–32. [42] Janjigian YY, Tang LH, Coit DG, Kelsen DP, Francone TD, Weiser MR, et al. MET expression and amplification in patients with localized gastric cancer. Cancer Epidermal Biomarkers Prev J 2011;20:1021–7. [43] Corso S, Comoglio PM, Giordano S. Cancer therapy: can the challenge be MET? Trends Mol Med J 2005;11:284–92. [44] Puri N, Salgia R. Synergism of EGFR and c-Met pathways, crosstalk and inhibiton, in non-small cell lung cancer. J Carcinog 2008;7:9. [45] Corso S, Ghiso E, Cepero V, Cepero V, Sierra JR, Migliore C, et al. Activation of HER family members in gastric carcinoma cells mediates resistance to MET inhibition. Mol Cancer J 2010;9:121.
Available online at
ScienceDirect www.sciencedirect.com
Review
The role of HER3 in gastric cancer Liying Wang, Hengheng Yuan, Yanjing Li, Yu Han * Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, Harbin, PR China
A R T I C L E I N F O
A B S T R A C T
Article history: Received 9 July 2014 Accepted 6 August 2014
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. ß 2014 Elsevier Masson SAS. All rights reserved.
Keywords: HER3 Gastric cancer Monoclonal antibody MET inhibitor
1. 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 5year 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,
* Corresponding author. Department of Gastrointestinal Oncology, The Third Affiliated Hospital, Harbin Medical University, 150 Haping St, Nangang District, Harbin 150081, PR China. Tel.: +86 451 86298268; fax: +86 451 86298689. E-mail address: [email protected] (Y. Han). http://dx.doi.org/10.1016/j.biopha.2014.08.011 0753-3322/ß 2014 Elsevier Masson SAS. All rights reserved.
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. 2. 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 heterodimer owing to binding with corresponding ligands triggers
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a complex signal transduction cascade, predominantly through phosphoinositide-3-kinase (PI3K)/Akt and extracellular signalregulated kinase1/2(ERK), adjusting the proliferation, migration, adhesion, angiogenesis, and apoptosis of cancer cells [12,13]. The HER2 receptor is distinguished with having no bind ligand, however, it preferred heterodimerization partner of the other HER family members, especially heterodimerized with HER3, and the HER2/HER3 heterodimer is likely to be the most effective complex for activating downstream pathways [14,15]. HER3, however, is encoded by the proto-oncogene c-ErbB3, which is a glycoprotein of 180 kDa. The HER3 gene is expressed as a 6.2- and a 1.4-kb transcript. The former encodes the full-length transmembrane protein and the latter unique truncated extracellular fragment is predicted to translate into a protein with 183 amino acids, of which the first 140 amino acids are similar to the Nterminus of HER3 and the 43 carboxy-terminal amino acids [16]. The HER3 full-length receptor has the characteristic extracellular domain structure as the same as the other family members, which consisted of four subdomains called L1 (I), C1 (II), L2 (III), and C2 (IV) [17]. Members of ErbB family interact with various ligands. As its name shows, EGFR has been suggested to interact with EGF as well as other ligands including betacellulin (BTC), epigen (EPG), epiregulin (EPR), transforming growth factor-a (TGF-a), amphiregulin (AR), and hearin-binding EGF-like growth factor (HB-EGF). It is known that HER3 has been found interacting with neuregulin (NRG)-1 and -2. HER3 is distinguished with the other ErbB family members by two points. First, HER3 is the unique one, which lacks a functioning kinase domain [18]. A large number of evidence suggests that even though HER3 is able to bind ATP, the phospho-transfer reaction is impaired catalytically [18]. Second, HER3 plays a crucial role in inducing the PI3K-AKT pathway to bind the PI3K p85 subunit through six consensus phosphotyrosine docking sites on its Cterminal [19,20]. As Osaki et al. proved that HER3 is essential to maintain PI3K/AKT signaling which induces gastric cancer cells proliferation [21]. It seems that HER3 activities as the key link between the receptor tyrosine kinase (RTK) and PI3K activation in RTK-driven tumors, such as gastric, colon, bladder, and non-small cell lung cancers. Li et al. investigated the mechanism through HER3 siRNA both in vitro and in vivo assay. To their surprise, HER3 knockdown is able to inhibit cell migration in vitro and metastasis in vivo by downregulating MMPs, specifically MMP1, MMP2 and MMP9 with regards to inactivation of PI3K/AKT signaling [22]. However, Seshagiri et al. surveyed the identification of HER3 somatic mutations in 11% and 12% of colon and gastric cancers, respectively. Most of the recurrent mutations are within the ECD (with a few located in the kinase domain). However, the mechanism by which ECD mutations activate HER3 is still unclear. Although a series of experiments in vivo and in vitro conclude that the presence of activating HER3 mutations increases the significance of HER3 in cancer [23]. Multiple evidences demonstrated that the transmission of EGFR homodimer signals is respectively weaker, and HER3 homodimer will never transform even in the presence of ligand. A majority of researches have shown that HER3 is the indispensible chaperones for HER2, which could induce tumor cell lines proliferation in breast cancers [24]. Overexpression of HER2 results in the increased formation of heterodimer. Moreover, the signal is examined as the most potent than any other homodimers or heterdimers. Interestingly, multiple studies reveal that as HER2 has no known ligand, and HER3’s intrinsic functions kinase is defective, so, they have been most readily complexes with each other. Within such tumor, the HER2–HER3 dimer has been demonstrated to be the greatest significance for tumor formation and tumor maintenance, furthermore, which is being the most mitogenic and transforming of them all [25–28]. In recent years,
more attentions have been paid to the relationships between HER3 and tumors, especially in breast cancer, ovarian cancer, esophageal cancer, laryngeal cancer, malignant melanoma and squamous cell carcinoma [29]. To our best knowledge, the role of HER3 in gastric cancer is relatively poor.
3. The role of HER3 in gastric cancer 3.1. 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 prognosis and a decreased survival [30]. Similarly, some authors used tissue microarray (TMA) for the reading of immunohistochemical analysis and fluorescence in situ hybridization (FISH), and employed different criteria for the interpretation of EGFR, HER3, HER4 expression. They observed that HER3 expression might have an impact on tumors progression, and HER3 expressed in the nucleus predicted poor survival [31]. Coincidentally, it has been demonstrated that HER3 has a significantly higher amplified rate in gastric cancer compared gastric cancer group with a nontumorous group (13.7% vs 2.0%, P < 0.01). It elucidated that overexpression of HER3 protein is not only involved in the process of gastric tumorigenesis, but also related to TNM stage and low survival rate [32]. In a recent study, Ocana et al. presented a metaanalysis aiming at evaluating the role of HER3 in relation to survival in solid tumors. They identified 12 studies that employed IHC techniques for the assessment of HER3 expression, suggesting that levels of HER3 overexpression in colorectal, gastric, and breast cancer ranging from 20% to 60%. What is more, there was a closer association between HER3 overexpression and detrimental outcome compared with normal HER3 expression, specially, most linked with gastric cancer [33]. Though considerable studies have been conducted to predict the prognostic value of HER3 overexpression of gastric cancer, the detailed mechanism has remained unclear. The latest investigation detected HER3 by means of both real-time PCR and IHC in 161 gastric cancer patients, and assessed its related downstream signaling PI3K/AKT activity and clinical characteristics by statistical analysis. In this study, HER3 knockdown inhibited gastric cancer cell lines proliferation, tumor growth and migration. However, it had no apparently impact on HER2 expression and activity [22]. This finding illustrated that HER3 was becoming an independent factor which predicts unfavorable prognosis and detrimental survival mediated by PI3K/AKT signaling pathway, and more attention should be paid on it as a potent candidate for molecular-targeted therapy in various types of gastric cancer. The prognostic role of HER3, however, has not yet reached a consensus. More recently, Jacome et al. performed a retrospective study including 201 patients with gastric and esophagogastric junction adenocacinoma stages 0–IV (AJCC 6th edition) who underwent primary tumor resection. Weibull distribution was used to analysis multivariate prognostic factors performed by a regression model. To our surprise, they clarified that there was no correlation between cytoplasmic HER3 expression and tumor depth, nodal metastases, or TNM stage. Moreover, the association among membrane HER3 expression, clinicopathological characteristics, and overall survival was not evaluated because of the 200 samples only one patient showed membrane positivity [34]. Some
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authors concluded that HER3 expression has been detected in both the intestinal type [32] and the diffuse type [31], but the association of prognostic in gastric cancer patients is still not intimately. The controversial results may be due to the methods for detecting HER3 expression are various and there is still no consensus about the criteria to be adopted for the reading of HER3 expression in gastric cancer. Overall, large prospective trials with validated methodology are needed to determine the real prognostic value of HER3 expression.
overcome resistance to HER2/MAPK/PI3K axis inhibition. They suggested that HER3 trans-phsphorylation and activation of HER3 dependent survival pathway contributed to the MET overexpression and constitutive activation, and HER3 may play a significant role in the acquisition of resistance to MET inhibition. Therefore, conclusion can be deduced that HER3 knockdown led to a reversion of the resistance to MET inhibitors [8,45].
3.2. HER3 and monoclonal antibody in gastric cancer
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 reliable and introduce a new era of personalized medicine.
It is known that HER3 has been disregarded as a cancer target due to the absence of intrinsic kinase activity in its intracellular domain. Thus, targeting the HER3 ECD through antibodies is becoming the focus. LJM716, a human anti-HER3 monoclonal antibody, is selective for an epitope created by domains II and IV of the HER3 ECD [35], which also inhibits ligand-induced and ligandindependent HER3 dimerization, as a single agent. Garrett et al. examined the effects of LJM716 through a series of experiments recently. In this study, they examined the impacts of LJM716 by different modes of aberrant PI3K pathway activation in cancer cells and xenografts in mice. They found LJM716 reduced HER2-HER3 and HER3-p85 dimers, p-HER3 and p-AKT, and delayed growth of HER2+ xenografts [36]. In this setting, additionally, LJM716 was proposed to significantly improve survival of mice when added to the doublet and synergistically induce cell death when given in combination with BY719, a PI3K inhibitor, which competes with ATP [37]. Furthermore, these data support the idea that a pure HER3 opponent to the disease in which HER3 is well established to mediate the PI3K pathway signal expressing oncoprotein as well as the key node of feedback regulation. More recently, fortunately, a large amount of direct evidence has emerged in a study examining the benefit of anti-HER3 agents in combination with EGFR tyrosine kinase inhibitors as well as anti-HER2 agents. Currently, EGFR and HER2 targeting was succeeded by a feedback upregulation of HER3 [38]. For instance, a preclinical study confirmed that HER3-PI3K axis may play a key role in survival of HER2-dependent cells and the ligand-lack HER2, and kinase-less HER3 may weaken the function of anti-HER2 therapy, what is more, targeting of HER3 and HER2 may act synergistically on the therapeutic value of HER2+ breast and gastric cancer patients [36–38]. Based on the data presented herein, the combination of a HER3 antibody that eliminates both ligand-dependent and -independent HER3 dimerization and an ATP competitive p110a inhibitor (BYL719) will be a strategy for dual blockade of HER2/HER3/PI3K axis [36]. 3.3. HER3 and MET in gastric cancer Recent studies have demonstrated that MET acts as the key in a high percentage of human tumors [39]. Evidences have illustrated that amplification of the MET gene and overexpression of the MET protein were observed in 10-20% of gastric cancer [40–42]. Due to the gene amplification associated with receptor overexpression, MET receptor is frequently constitutively activated. Several studies have shown a crosstalk between MET and HER family members in the context of the acquisition of a biochemical and functional interplay, such as in the MKN-45 gastric cell line [43,44]. Since MET-independent activation of the MAPK or PI3K pathways may drive cells ‘‘addicted’’ to oncogene, so targeting MET has been taken into account in recent studies. However, MET reactivating the pathway above will be critically overlapping with those generated by HER members, which induces the resistance to the targeting agents. Corso et al. investigated the mechanisms, which provided a rationale for the use of MET inhibitors to
4. Conclusion
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. References [1] Jemal A, Center MM, DeSantis C, Ward EM. Global patterns of cancer incidence and mortality rates and trends. J Cancer Epidermal Biomarkers Prev 2010;19:1893–907. [2] Inoue M, Tsugane S. Epidemiology of gastric cancer in Japan. Postgrad J Med 2005;81:419–24. [3] Siegel R, Naishadham D, Jemal A. Cancer statistics CA Cancer. J Clin 2013;63:11–30. [4] Nashimoto A, Akazawa K, Isobe Y, Miyashiro I, Katai H, Kodera Y, et al. Gastric cancer treated in 2002 in Japan: 2009 annual report of the JGCA nationwide registry. J Gastric Cancer 2013;16:1–27. [5] Shimoyama S. Unraveling trastuzumab and lapatinib inefficiency in gastric cancer: future steps. J Mol Clin Oncol 2014;2:175–81. [6] Weinstein IB, Joe AK. Mechanisms of disease: oncogene addiction a rationale for molecular targeting in cancer therapy. J Nat Clin Pract Oncol 2006;3:448– 57. [7] Gravalos C, Jimeno A. HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. J Ann Oncol 2008;19:1523–9. [8] Herbst RS, Shin DM. Monoclonal antibodies to target epidermal growth factor receptor-positive tumors: a new paradigm for cancer therapy. J Cancer 2002;94(5):593–1611. [9] Olayioye MA, Neve RM, Lane HA, Hynes NE. The ErbB signaling network: receptor heterodimerization in development and cancer. J EMBO 2010;19:3159–67. [10] Schlessinger J. Common and distinct elements is cellular signaling via EGF and FGF receptors. J Sci 2004;306:1506–7. [11] Han W, Lo HW. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett J 2012;318:124–34. [12] Yokoyama H, Ikehara Y, Kodera Y, Ikehara S, Yatabe Y, Mochizuki Y, et al. Molecular basis for sensitivity and acquired resistance to gefitinib in HER2 overexpression human gastric cancer cell lines derived from liver metastasis. Br J Cancer 2006;95:1504–13. [13] Pratilas CA, Hanrahan AJ, Halilovic E, Persaud Y, Soh J, Chitale D, et al. Genetic predictors of MEK dependence in non-small cell lung cancer. Cancer Res J 2008;68:9375–83. [14] Lesma E, Grande V, Ancona S, Carelli S, Maria A, Giulio D, et al. Anti-EGFR antibody efficiently and specifically inhibits human TSC2/smooth muscle cell proliferation: possible treatment options for TSC and LAM. PloS One 2008;3:e3558.
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