Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

Sukawa, Yasutaka; Yamamoto, Hiroyuki; Nosho, Katsuhiko; Kunimoto, Hiroaki; Suzuki, Hiromu; Adachi, Yasushi; Nakazawa, Mayumi; Nobuoka, Takayuki; Kawayama, Mariko; Mikami, Masashi; Matsuno, T.; Hasegawa, Tadashi; Hirata, Koichi; Imai, Kohzoh; Shinomura, Yasuhisa

doi:10.3748/wjg.v18.i45.6577

Cited by 73 publications

(64 citation statements)

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“…Furthermore, in concordance with prior data [35,36], the study revealed a strong predilection for PIK3CA mutation in EBV positive tumors, with nonsilent PIK3CA mutations found in 80% of this subgroup (P < 0.001), that could be targeted using PI(3)-kinase inhibition.…”

Section: Molecular Classiication Of Gastric Cancers By "The Cancer Gesupporting

confidence: 71%

Molecular Prognostic Factors in Gastric Cancer

Lazăr¹,

Tăban²,

Cornianu³

et al. 2017

Gastric Cancer

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Gastric cancer represents a major health problem worldwide. Literature data have demonstrated that gastric tumors present a high molecular heterogeneity, responsible for the process of carcinogenesis and dissemination. By revealing the molecular subtype of the tumor, it is possible to assess its behavior, the outcome of the patient, and the treatment approach, according to its genetic and epigenetic proile. This chapter aims to highlight some of the many diferent genetic mutations, epigenetic alterations, as well as aberrant signaling pathways involved in the pathogenesis of stomach cancers, each of these molecular abnormalities acting in a speciic stage of the disease. Moreover, the manuscript describes the novel therapeutic agents that target some of these aberrant molecular signaling pathways. Unfortunately, only a few agents are currently part of the standard treatment of gastric cancer, while most of the others remain to prove their therapeutic eicacy in the seting of clinical trials. By discovering the diferent molecular subtypes of gastric cancer, as well as numerous classes of targeted molecular agents, in the future, we would be able to perform an individualized treatment, associated with maximum eiciency and less costs.Keywords: gastric cancer, molecular classiication, gene expressions-based prognostic scoring system, molecular biomarkers, molecular targeted treatment IntroductionDespite a decline in the incidence in past decades, gastric cancer remains a major health problem globally [1,2], being the ifth most common type of cancer worldwide, with almost one million new cases estimated to have occurred in 2012, according to Globocan [3]. Furthermore, stomach cancer represents the third leading cause of cancer death in both sexes worldwide (723,000 deaths) [3].© 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.According to the World Health Organization classiication, the vast majority of gastric cancers are adenocarcinomas, divided into papillary, tubular, mucinous (colloid), and poorly cohesive carcinomas (including signet-ring cell carcinoma and other variants) [4]. Although it was proposed a long time ago (1965), the Lauren classiication is still widely used in clinical practice and subdivides gastric carcinomas into intestinal and difuse types, associated with diferent pathogenesis, ways of spreading, and outcome [5]. Unfortunately, these two classiication systems have litle clinical impact, making the development of classiiers that can deine prognosis and guide patient's treatment as an urgent need.Literature data have demonstrated that the development of gastric cancer is associated in the majority of cases with infectious agents such as the Gram-negative spiral bacterium Helicobacter pylori (most often) [6] and Epstein-Barr virus (EBV) (about 9% o...

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Section: Molecular Classiication Of Gastric Cancers By "The Cancer Gesupporting

confidence: 71%

Molecular Prognostic Factors in Gastric Cancer

Lazăr¹,

Tăban²,

Cornianu³

et al. 2017

Gastric Cancer

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“…Patients testing positive for the abnormal expression of the PI3K/AKT/mTOR pathway were more likely to be in the late stages of gastric cancer with a lower survival rate. [4][5][6][7] Several drugs targeting PI3K/AKT/mTOR pathways are currently in clinical trials for gastric cancer, including PI3K inhibitor (LY294002, MK2206), AKT inhibitor (MLN1117), and mTOR inhibitor (everolimus). [8][9][10][11] PI3K inhibitor and AKT inhibitor monotherapy showed promising effects in Phases I-II, while mTOR inhibitor failed to improve survival in the GRANITE-1 Stage III trial for advanced gastric cancer.…”

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confidence: 99%

“…A score 4 was considered to be positive. 4,5,7 statistical analysis Statistical Package for the Social Sciences (SPSS) version 16.0 (SPSS Inc., Chicago, IL, USA) was used for the statistical analysis. The correlation between PI3K, p-AKT, and p-mTOR expression and patient clinicopathologic factors was analyzed using the χ 2 test.…”

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confidence: 99%

2381 The expression of the PI3K/AKT/mTOR pathway in gastric cancer and its role in gastric cancer prognosis

Ying¹,

He²,

Sun³

et al. 2015

European Journal of Cancer

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“…Due to its important role in cancer, there is great interest in the development of inhibitors able to target on the signaling pathways in preclinical trials. Sukawa et al (19) detected the expression of p-Akt in the tissue specimens of 231 patients with gastric cancer, and identified that 53% gastric cancer tissue specimens exhibit p-Akt expression and that patients with p-Akt expression demonstrate poor prognoses. An additional previous study suggested that the expression of p-Akt in 45 gastric cancer tissue specimens was up to 82.2%, and associated with tumor growth and metastasis (20).…”

Section: Discussionmentioning

confidence: 99%

Combination of cecropinXJ and LY294002 induces synergistic cytotoxicity, and apoptosis in human gastric cancer cells via inhibition of the PI3K/Akt signaling pathway

Zhang

2017

Oncol Lett

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Abstract. The aim of the present study was to investigate the cytotoxic and apoptotic effects of cecropinXJ against human gastric cancer BGC823 cells, either alone, or in combination with a specific phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002. Cell viability and the apoptosis rate were measured using flow cytometry with Annexin-V staining. Additionally, the expression levels of several RAC-α serine/threonine kinase (Akt) phosphorylation-associated proteins and apoptosis-regulating proteins were evaluated by western blot analysis. It was observed that the combination of cecropinXJ and LY294002 resulted in significant synergistic cytotoxic and apoptosis effects, as compared with any single agent alone, in a dose-dependent manner. Corresponding to enhanced apoptosis, the expression levels of certain apoptosis-regulating proteins were changed, the most notable being the upregulation of caspase-3, B-cell lymphoma-2 (Bcl-2)-associated death promotor, Bcl-2 homologous antagonist killer, Bcl-2 interacting killer, Bcl-2-like protein 11, Bcl-2-like protein 4 and cytochrome c, and the downregulation of phosphorylated-Bad and Bcl-2 proteins. The present study provided a novel therapeutic regimen for the use of the cecropinXJ in combination with LY294002 for the treatment of gastric cancer.

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Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer

Abstract: HER2 expression, PIK3CA mutations and EBV infection in gastric cancer were characterized. pAkt expression significantly correlates with HER2 expression and with a poor prognosis.

Cited by 73 publications

References 36 publications

Molecular Prognostic Factors in Gastric Cancer

Molecular Prognostic Factors in Gastric Cancer

2381 The expression of the PI3K/AKT/mTOR pathway in gastric cancer and its role in gastric cancer prognosis

Combination of cecropinXJ and LY294002 induces synergistic cytotoxicity, and apoptosis in human gastric cancer cells via inhibition of the PI3K/Akt signaling pathway

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