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Sun Y, Puspanathan P, Lim T, Lin D. Advances and challenges in gastric cancer testing: the role of biomarkers. Cancer Biol Med 2025; 22:j.issn.2095-3941.2024.0386. [PMID: 40126094 PMCID: PMC11976707 DOI: 10.20892/j.issn.2095-3941.2024.0386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 01/23/2025] [Indexed: 03/25/2025] Open
Abstract
Advances in the identification of molecular biomarkers and the development of targeted therapies have enhanced the prognosis of patients with advanced gastric cancer. Several established biomarkers have been widely integrated into routine clinical diagnostics of gastric cancer to guide personalized treatment. Human epidermal growth factor receptor 2 (HER2) was the first molecular biomarker to be used in gastric cancer with trastuzumab being the first approved targeted therapy for HER2-positive gastric cancer. Programmed death-ligand 1 positivity and microsatellite instability can guide the use of immunotherapies, such as pembrolizumab and nivolumab. More recently, zolbetuximab has been approved for patients with claudin 18.2-positive diseases in some countries. More targeted therapies, including savolitinib for MET-positive patients, are currently under clinical investigation. However, the clinical application of these diagnostic approaches could be hampered by many existing challenges, including invasive and costly sampling methods, variability in immunohistochemistry interpretation, high costs and long turnaround times for next-generation sequencing, the absence of standardized and clinically validated diagnostic cut-off values for some biomarkers, and tumor heterogeneity. Novel testing and analysis techniques, such as artificial intelligence-assisted image analysis and multiplex immunohistochemistry, and emerging therapeutic strategies, including combination therapies that integrate immune checkpoint inhibitors with targeted therapies, offer potential solutions to some of these challenges. This article reviews recent progress in gastric cancer testing, outlines current challenges, and explores future directions for biomarker testing and targeted therapy for gastric cancer.
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Affiliation(s)
- Yu Sun
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | | | - Tony Lim
- Division of Pathology, Singapore General Hospital, Singapore 169608, Singapore
| | - Dongmei Lin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Zhang B, Chen X, Song H, Gao X, Ma S, Ji H, Qu H, Xia S, Shang D. Identification of basement membrane-related prognostic model associated with the immune microenvironment and synthetic therapy response in pancreatic cancer: integrated bioinformatics analysis and clinical validation. J Cancer 2024; 15:6273-6298. [PMID: 39513120 PMCID: PMC11540510 DOI: 10.7150/jca.100891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 09/28/2024] [Indexed: 11/15/2024] Open
Abstract
Pancreatic cancer (PC) is a common and highly malignant tumor. Basement membrane (BM) is formed by the crosslinking of extracellular matrix macromolecules and acts as a barrier against tumor cell metastasis. However, the role of BM in PC prognosis, immune infiltration, and treatment remains unclear. This study collected transcriptome and clinical survival data of PC via TCGA, GEO, and ICGC databases. PC patients (PCs) from the First Affiliated Hospital of Dalian Medical University were obtained as the clinical validation cohort. BM-related genes (BMRGs) were acquired from GeneCards and basement membraneBASE databases. A total of 46 differential-expressed BMRGs were identified. Then the BM-related prognostic model (including DSG3, MET, and PLAU) was built and validated. PCs with a low BM-related score had a better outcome and were more likely to benefit from oxaliplatin, irinotecan, and KRAS(G12C) inhibitor-12, and immunotherapy. Immune analysis revealed that BM-related score was positively correlated with neutrophils, cancer-associated fibroblasts, and macrophages infiltration, but negatively correlated with CD8+ T cells, NK cells, and B cells infiltration. PCs from the clinical cohort further verified that BM-related model could accurately predict PCs' outcomes. DSG3, MET, and PLAU were notably up-regulated within PC tissues and linked to a poor prognosis. In vitro experiments showed that DSG3 knockdown markedly suppressed the proliferation, migration, and invasion of PC cells. Molecular docking indicated that epigallocatechin gallate had a strong binding activity with DSG3, MET, and PLAU and may be used as a potential therapeutic agent for PC. In conclusion, this study developed a BM-related model associated with PC prognosis, immune infiltration, and treatment, which provided new insights into PC stratification and drug intervention.
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Affiliation(s)
- Biao Zhang
- Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Xu Chen
- Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Huiyi Song
- Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Xue Gao
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shurong Ma
- Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Hongying Ji
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Huixian Qu
- Department of Pathology, The First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Shilin Xia
- Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
| | - Dong Shang
- Pancreas & Biliary Center, Department of General Surgery, Clinical Laboratory of Integrative Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, China
- Institute (College) of Integrative Medicine, Dalian Medical University, Dalian, China
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Wei WJ, Hong YL, Deng Y, Wang GL, Qiu JT, Pan F. Research progress on the development of hepatocyte growth factor/c-Met signaling pathway in gastric cancer: A review. World J Gastrointest Oncol 2024; 16:3397-3409. [PMID: 39171189 PMCID: PMC11334049 DOI: 10.4251/wjgo.v16.i8.3397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 05/31/2024] [Accepted: 06/21/2024] [Indexed: 08/07/2024] Open
Abstract
Hepatocyte growth factor (HGF) and its receptor, c-Met, play important roles in the occurrence, development, and treatment of gastric cancer (GC). This review explored the function of the HGF/c-Met signaling pathway in GC and its potential targeted therapeutic mechanisms. As one of the most common malignant tumors worldwide, GC has a complex pathogenesis and limited therapeutic options. Therefore, a thorough understanding of the molecular mechanism of GC is very important for the development of new therapeutic methods. The HGF/c-Met signaling pathway plays an important role in the proliferation, migration, and invasion of GC cells and has become a new therapeutic target. This review summarizes the current research progress on the role of HGF/c-Met in GC and discusses targeted therapeutic strategies targeting this signaling pathway, providing new ideas and directions for the treatment of GC.
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Affiliation(s)
- Wu-Jie Wei
- Department of Oncology, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Ya-Li Hong
- Department of Cardiovascular, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Yi Deng
- Intensive Care Unit, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Guan-Liang Wang
- Department of Oncology, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
| | - Jiang-Tao Qiu
- Department of Gastrointestinal Surgery, Beijing Tsinghua Changgung Hospital, Beijing 100084, China
| | - Fang Pan
- Department of Oncology, People's Hospital of Chongqing Hechuan, Chongqing 401520, China
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Wang LM, Zhang WW, Qiu YY, Wang F. Ferroptosis regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. World J Gastrointest Oncol 2024; 16:2781-2792. [PMID: 38994139 PMCID: PMC11236228 DOI: 10.4251/wjgo.v16.i6.2781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 03/06/2024] [Accepted: 04/10/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Gastric cancer is one of the most common malignant tumors in the world, and its occurrence and development involve complex biological processes. Iron death, as a new cell death mode, has attracted wide attention in recent years. However, the regulatory mechanism of iron death in gastric cancer and its effect on lipid peroxidation metabolism remain unclear. AIM To explore the role of iron death in the development of gastric cancer, reveal its relationship with lipid peroxidation, and provide a new theoretical basis for revealing the molecular mechanism of the occurrence and development of gastric cancer. METHODS The process of iron death in gastric cancer cells was simulated by cell culture model, and the occurrence of iron death was detected by fluorescence microscopy and flow cytometry. The changes of gene expression related to iron death and lipid peroxidation metabolism were analyzed by high-throughput sequencing technology. In addition, a mouse model of gastric cancer was established, and the role of iron death in vivo was studied by histology and immunohistochemistry, and the level of lipid peroxidation was detected. These methods comprehensively and deeply reveal the regulatory mechanism of iron death on lipid peroxidation metabolism in the occurrence and development of gastric cancer. RESULTS Iron death was significantly activated in gastric cancer cells, and at the same time, associated lipid peroxidation levels increased significantly. Through high-throughput sequencing analysis, it was found that iron death regulated the expression of several genes related to lipid metabolism. In vivo experiments demonstrated that increased iron death in gastric cancer mice was accompanied by a significant increase in lipid peroxidation. CONCLUSION This study confirmed the important role of iron death in regulating lipid peroxidation metabolism in the occurrence and development of gastric cancer. The activation of iron death significantly increased lipid peroxidation levels, revealing its regulatory mechanism inside the cell.
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Affiliation(s)
- Lan-Mei Wang
- Department of Clinical Laboratory, Anqiu People's Hospital, Weifang 262123, Shandong Province, China
| | - Wei-Wei Zhang
- Department of Gastroenterology, Feicheng People's Hospital, Tai’an 271600, Shandong Province, China
| | - Ying-Yang Qiu
- Yong Loo Lin School of Medicine, National University of Singapore, 119077, Singapore
| | - Fang Wang
- Department of Gastroenterology, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, Shandong Province, China
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Lombardi AM, Sangiolo D, Vigna E. MET Oncogene Targeting for Cancer Immunotherapy. Int J Mol Sci 2024; 25:6109. [PMID: 38892318 PMCID: PMC11173045 DOI: 10.3390/ijms25116109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 05/29/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
The MET receptor is one of the main drivers of 'invasive growth', a multifaceted biological response essential during embryonic development and tissue repair that is usurped by cancer cells to induce and sustain the malignant phenotype. MET stands out as one of the most important oncogenes activated in cancer and its inhibition has been explored since the initial era of cancer-targeted therapy. Different approaches have been developed to hamper MET signaling and/or reduce MET (over)expression as a hallmark of transformation. Considering the great interest gained by cancer immunotherapy, this review evaluates the opportunity of targeting MET within therapeutic approaches based on the exploitation of immune functions, either in those cases where MET impairment is crucial to induce an effective response (i.e., when MET is the driver of the malignancy), or when blocking MET represents a way for potentiating the treatment (i.e., when MET is an adjuvant of tumor fitness).
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Affiliation(s)
| | | | - Elisa Vigna
- Department of Oncology, University of Torino, 10043 Torino, Italy; (A.M.L.); (D.S.)
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Kim JS, Kim MY, Hong S. Characterization of MET Alterations in 37 Gastroesophageal Cancer Cell Lines for MET-Targeted Therapy. Int J Mol Sci 2024; 25:5975. [PMID: 38892160 PMCID: PMC11173193 DOI: 10.3390/ijms25115975] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 05/26/2024] [Accepted: 05/28/2024] [Indexed: 06/21/2024] Open
Abstract
Capmatinib and savolitinib, selective MET inhibitors, are widely used to treat various MET-positive cancers. In this study, we aimed to determine the effects of these inhibitors on MET-amplified gastric cancer (GC) cells. Methods: After screening 37 GC cell lines, the following cell lines were found to be MET-positive with copy number variation >10: SNU-620, ESO51, MKN-45, SNU-5, and OE33 cell lines. Next, we assessed the cytotoxic response of these cell lines to capmatinib or savolitinib alone using cell counting kit-8 and clonogenic cell survival assays. Western blotting was performed to assess the effects of capmatinib and savolitinib on the MET signaling pathway. Xenograft studies were performed to evaluate the in vivo therapeutic efficacy of savolitinib in MKN-45 cells. Savolitinib and capmatinib exerted anti-proliferative effects on MET-amplified GC cell lines in a dose-dependent manner. Savolitinib inhibited the phosphorylation of MET and downstream signaling pathways, such as the protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways, in MET-amplified GC cells. Additionally, savolitinib significantly decreased the number of colonies formed on the soft agar and exerted dose-dependent anti-tumor effects in an MKN-45 GC cell xenograft model. Furthermore, a combination of trastuzumab and capmatinib exhibited enhanced inhibition of AKT and ERK activation in human epidermal growth factor receptor-2 (HER2)- and MET-positive OE33 cells. Targeting MET with savolitinib and capmatinib efficiently suppressed the growth of MET-amplified GC cells. Moreover, these MET inhibitors exerted synergistic effects with trastuzumab on HER2- and MET-amplified GC cells.
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Affiliation(s)
- Jin-Soo Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Mi Young Kim
- Department of Internal Medicine, Seoul National University Boramae Medical Center, Seoul 07061, Republic of Korea;
| | - Sungyoul Hong
- College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea;
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Weng ZY, Huang WY, Shi BK, Pan JJ. Role of savolitinib in advanced gastric adenocarcinoma with meningeal carcinomatosis and cerebellar metastasis: A case report. World J Clin Cases 2024; 12:2636-2641. [PMID: 38817213 PMCID: PMC11135453 DOI: 10.12998/wjcc.v12.i15.2636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2024] [Revised: 02/14/2024] [Accepted: 04/07/2024] [Indexed: 05/14/2024] Open
Abstract
BACKGROUND Brain metastases (BM) are very rare in gastric adenocarcinoma (GaC), and patients with BMs have a higher mortality rate due to stronger tumor aggressiveness. However, its pathogenesis remains unclear. Genetic testing revealed cellular-mesenchymal epithelial transition factor receptor (MET) amplification. Therefore, treatment with savolitinib, a small molecule inhibitor of c-Met, was selected. CASE SUMMARY A 66-year-old woman was diagnosed with advanced GaC 6 months prior to presentation due to back pain. Cerebellar and meningeal metastases were observed during candonilimab combined with oxaliplatin and capecitabine therapy. The patient experienced frequent generalized seizures and persistent drowsiness in the emergency department. Genetic testing of cerebrospinal fluid and peripheral blood revealed increased MET amplification. After discussing treatment options with the patient, savolitinib tablets were administered. After a month of treatment, the intracranial lesions shrank considerably. CONCLUSION BM is very rare in advanced GaC, especially in meningeal cancer, that is characterized by rapid disease deterioration. There are very few effective treatment options available; however, technological breakthroughs in genomics have provided a basis for personalized treatment. Furthermore, MET amplification may be a key driver of BM in gastric cancer; however, this conclusion requires further investigation.
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Affiliation(s)
- Zhi-Yun Weng
- Department of Hematology, The Affiliated Yueqing Hospital of Wenzhou Medical University, Yueqing 325600, Zhejiang Province, China
| | - Wen-Ye Huang
- Department of Hematology, The Affiliated Yueqing Hospital of Wenzhou Medical University, Yueqing 325600, Zhejiang Province, China
| | - Bin-Kan Shi
- Department of Hematology, The Affiliated Yueqing Hospital of Wenzhou Medical University, Yueqing 325600, Zhejiang Province, China
| | - Jian-Jia Pan
- Department of Hematology, The Affiliated Yueqing Hospital of Wenzhou Medical University, Yueqing 325600, Zhejiang Province, China
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8
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Zhang Y, Shen L, Peng Z. Advances in MET tyrosine kinase inhibitors in gastric cancer. Cancer Biol Med 2024; 21:j.issn.2095-3941.2024.0044. [PMID: 38727001 PMCID: PMC11208904 DOI: 10.20892/j.issn.2095-3941.2024.0044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Accepted: 04/11/2024] [Indexed: 06/29/2024] Open
Abstract
Gastric cancer is among the most frequently occurring cancers and a leading cause of cancer-related deaths globally. Because gastric cancer is highly heterogenous and comprised of different subtypes with distinct molecular and clinical characteristics, the management of gastric cancer calls for better-defined, biomarker-guided, molecular-based treatment strategies. MET is a receptor tyrosine kinase mediating important physiologic processes, such as embryogenesis, tissue regeneration, and wound healing. However, mounting evidence suggests that aberrant MET pathway activation contributes to tumour proliferation and metastasis in multiple cancer types, including gastric cancer, and is associated with poor patient outcomes. As such, MET-targeting therapies are being actively developed and promising progress has been demonstrated, especially with MET tyrosine kinase inhibitors. This review aims to briefly introduce the role of MET alterations in gastric cancer and summarize in detail the current progress of MET tyrosine kinase inhibitors in this disease area with a focus on savolitinib, tepotinib, capmatinib, and crizotinib. Building on current knowledge, this review further discusses existing challenges in MET alterations testing, possible resistance mechanisms to MET inhibitors, and future directions of MET-targeting therapies.
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Affiliation(s)
- Yifan Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lin Shen
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhi Peng
- State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Koike Y, Osakabe M, Sugimoto R, Uesugi N, Matsumoto T, Suzuki H, Yanagawa N, Sugai T. A genome-wide study of gastric intramucosal neoplasia based on somatic copy number alterations, gene mutations, and mRNA expression patterns. J Pathol Clin Res 2024; 10:e12368. [PMID: 38454538 PMCID: PMC10920940 DOI: 10.1002/2056-4538.12368] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/20/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024]
Abstract
We performed comprehensive analyses of somatic copy number alterations (SCNAs) and gene expression profiles of gastric intramucosal neoplasia (IMN) using array-based methods in 97 intestinal-type IMNs, including 39 low-grade dysplasias (LGDs), 37 high-grade dysplasias (HGDs), and 26 intramucosal carcinomas (IMCs) with stromal invasion of the lamina propria to identify the molecular mechanism of IMN. In addition, we examined gene mutations using gene panel analyses. We used cluster analyses for exclusion of arbitrariness to identify SCNA patterns and expression profiles. IMNs were classified into two distinct subgroups (subgroups 1 and 2) based on SCNA patterns. Subgroup 1 showed a genomic stable pattern due to the low frequency of SCNAs, whereas subgroup 2 exhibited a chromosomal instability pattern due to the high frequencies of SCNAs and TP53 mutations. Interestingly, although the frequencies of LGD and HGD were significantly higher in subgroup 1 than in subgroup 2, IMC was commonly found in both types. Although the expression profiles of specific mRNAs could be used to categorise subgroups 1 and 2, no clinicopathological findings correlated with either subgroup. We examined signalling pathways specific to subgroups 1 and 2 to identify the association of each subgroup with signalling pathways based on gene ontology tree visualisation: subgroups 1 and 2 were associated with haem metabolism and chromosomal instability, respectively. These findings reveal a comprehensive genomic landscape that highlights the molecular complexity of IMNs and provide a road map to facilitate our understanding of gastric IMNs.
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Affiliation(s)
- Yoshihiko Koike
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Noriyuku Uesugi
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
- Diagnostic Pathology CenterSouthern Tohoku General HospitalKooriyamaJapan
| | - Takayuki Matsumoto
- Division of GastroenterologyDepartment of Internal MedicineShiwagun'yahabachouJapan
| | - Hiromu Suzuki
- Department of Molecular BiologySapporo Medical University, School of MedicineSapporoJapan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of MedicineIwate Medical UniversityShiwagun'yahabachouJapan
- Diagnostic Pathology CenterSouthern Tohoku General HospitalKooriyamaJapan
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Byeon S, Jung J, Kim ST, Kim KM, Lee J. Clinical Implication of Concurrent Amplification of MET and FGFR2 in Metastatic Gastric Cancer. Biomedicines 2023; 11:3172. [PMID: 38137393 PMCID: PMC10740780 DOI: 10.3390/biomedicines11123172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/24/2023] Open
Abstract
BACKGROUND c-mesenchymal epithelial transition factor receptor (c-MET) and fibroblast growth factor receptor 2 (FGFR2) amplification have been identified as factors associated with advanced stage and poor prognosis in gastric cancer (GC). While they are typically considered mutually exclusive, concurrent amplifications have been reported in a small subset of GC patients. METHODS in this retrospective study, we analyzed the clinical outcomes of GC patients with MET and FGFR2 amplification using the next-generation sequencing (NGS) database cohort at Samsung Medical Center, which included a total of 2119 patients between October 2019 and April 2021. RESULTS Of 2119 cancer patients surveyed, the number of GC patients was 614 (29.0%). Out of 614 GC patients, 39 (6.4%) had FGFR2 amplification alone, 22 (3.6%) had MET amplification, and 2 GC patients (0.3%) had concurrent FGFR2 and MET amplification. Two patients with concurrent FGFR2 and MET amplification did not respond to first-line chemotherapy. These two patients had significantly shorter overall survival (3.6 months) compared to patients with FGFR2 or MET amplification alone (13.6 months and 8.4 months, respectively) (p = 0.004). Lastly, we tested the existence of FGFR2 and MET in tumor specimens from different organ sites. Initially, the NGS was tested in a primary tumor specimen from stomach cancer, where the MET copy number was 14.1 and the FGFR2 copy number was 5.3. We confirmed that both MET and FGFR2 were highly amplified in the primary tumor using FISH (MET-CEP7 ratio = 5 and FGFR2-CEP7 ratio = 3). However, although the MET copy number was normal in peritoneal seeding using FISH, FGFR2 remained amplified using FISH (FGFR2-CEP7 ratio = 7) with high FGFR2 protein overexpression. Hence, there was intra-patient molecular heterogeneity. CONCLUSIONS our findings suggest that concurrent amplification of FGFR2 and MET in GC patients is associated with clinical aggressiveness and may contribute to non-responsiveness to chemotherapy or targeted therapy.
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Affiliation(s)
- Seonggyu Byeon
- Division of Hematology-Oncology, Department of Internal Medicine, Ewha Womans University Seoul Hospital, Seoul 07804, Republic of Korea;
| | - Jaeyun Jung
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Seung Tae Kim
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;
| | - Jeeyun Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea
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11
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Kumaki Y, Oda G, Ikeda S. Targeting MET Amplification: Opportunities and Obstacles in Therapeutic Approaches. Cancers (Basel) 2023; 15:4552. [PMID: 37760522 PMCID: PMC10526812 DOI: 10.3390/cancers15184552] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 09/01/2023] [Accepted: 09/11/2023] [Indexed: 09/29/2023] Open
Abstract
The MET gene plays a vital role in cellular proliferation, earning it recognition as a principal oncogene. Therapies that target MET amplification have demonstrated promising results both in preclinical models and in specific clinical cases. A significant obstacle to these therapies is the ability to distinguish between focal amplification and polysomy, a task for which simple MET copy number measurement proves insufficient. To effectively differentiate between the two, it is crucial to utilize comparative measures, including in situ hybridization (ISH) with the centromere or next generation sequencing (NGS) with adjacent genes. Despite the promising potential of MET amplification treatment, the judicious selection of patients is paramount to maximize therapeutic efficacy. The effectiveness of MET inhibitors can fluctuate depending on the extent of MET amplification. Future research must seek to establish the ideal threshold value for MET amplification, identify the most efficacious combination therapies, and innovate new targeted treatments for patients exhibiting MET amplification.
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Affiliation(s)
- Yuichi Kumaki
- Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
| | - Goshi Oda
- Department of Specialized Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan;
| | - Sadakatsu Ikeda
- Center for Innovative Cancer Treatment, Tokyo Medical and Dental University, Tokyo 113-8519, Japan
- Moores Cancer Center, University of California San Diego, La Jolla, CA 92037, USA
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Shin M, Ahn S, Jung J, Hyung S, Kim K, Kim ST, Kang WK, Lee J. Impact of programmed death-ligand 1 (PD-L1) positivity on clinical and molecular features of patients with metastatic gastric cancer. Cancer Med 2023; 12:18633-18642. [PMID: 37654198 PMCID: PMC10557860 DOI: 10.1002/cam4.6472] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 07/13/2023] [Accepted: 08/11/2023] [Indexed: 09/02/2023] Open
Abstract
BACKGROUND Programmed death-ligand 1 (PD-L1) is an important screening biomarker to select patients with gastric cancer (GC) for optimized treatment, including immune checkpoint inhibitors (ICI). METHODS In this single-institution retrospective cohort study, patients with metastatic GC with available PD-L1 results between October 2019 and September 2021 were identified by reviewing their electronic medical records. Genomic data were obtained from the Samsung Medical Center Clinical Sequencing Platform. RESULTS Among the 399 patients, 276 (69%) had a PD-L1 combined positive score (CPS) ≥1, 155 (39%) had a CPS between 1 and 5, and 121 (30%) had a CPS ≥5. Of the 121 patients with CPS ≥5, 28 (23%) had a known etiology for "inflamed tumor," with Epstein-Barr virus (EBV) positivity (N = 11) or high tumor mutational burden (TMB) (N = 17), which included microsatellite instability (MSI) (N = 9). PD-L1 CPS ≥5 was observed in 11/11 (100%) patients with EBV positivity, 9/12 (75%) patients with MSI, and 17/33 (52%) patients with high TMB. For the 108 patients who received ICI therapy, CPS ≥5 was the only predictor significantly associated with survival in multivariable analyses, including TMB, MSI, or EBV. Objective response rate (ORR) was 49% in patients with CPS ≥5, 30% in patients with 1 ≤ CPS <5, and 19% in patients with CPS <1. Among the 31 responders to ICI therapy, 27 (87%) had a CPS of ≥1. Mutations in TET2, IRS2, DOT1L, PTPRT, and LRP1B were associated with a higher ORR (63%-100%), whereas MDC1 mutations were associated with a low ORR (22%). CONCLUSIONS PD-L1 expression is an independent and sensitive biomarker for ICI therapy. Considering its significant association with several gene alterations, including PIK3CA mutations and MET amplification, combining ICI therapy with other targeted agents may be a promising therapeutic strategy for GC.
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Affiliation(s)
- Minkyue Shin
- Division of Hematology‐Oncology, Department of MedicineSungkyunkwan University School of Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Soomin Ahn
- Department of Pathology and Translational GenomicsSungkyunkwan University School of Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Jaeyun Jung
- Innovative Institute for Precision Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Sujin Hyung
- Innovative Institute for Precision Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Kyoung‐Mee Kim
- Department of Pathology and Translational GenomicsSungkyunkwan University School of Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Seung Tae Kim
- Division of Hematology‐Oncology, Department of MedicineSungkyunkwan University School of Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Won Ki Kang
- Division of Hematology‐Oncology, Department of MedicineSungkyunkwan University School of Medicine, Samsung Medical CenterSeoulSouth Korea
| | - Jeeyun Lee
- Division of Hematology‐Oncology, Department of MedicineSungkyunkwan University School of Medicine, Samsung Medical CenterSeoulSouth Korea
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13
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Van Herpe F, Van Cutsem E. The Role of cMET in Gastric Cancer—A Review of the Literature. Cancers (Basel) 2023; 15:cancers15071976. [PMID: 37046637 PMCID: PMC10093530 DOI: 10.3390/cancers15071976] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 03/10/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
Gastric cancer (GC) is an important cause of cancer worldwide with over one million new cases yearly. The vast majority of cases present in stage IV disease, and it still bears a poor prognosis. However, since 2010, progress has been made with the introduction of targeted therapies against HER2 and with checkpoint inhibitors (PDL1). More agents interfering with other targets (FGFR2B, CLDN18.2) are being investigated. cMET is a less frequent molecular target that has been studied for gastric cancer. It is a proto-oncogene that leads to activation of the MAPK pathway and the PI3K pathway, which is responsible for activating the MTOR pathway. The prevalence of cMET is strongly debated as different techniques are being used to detect MET-driven tumors. Because of the difference in diagnostic assays, selecting patients who benefit from cMET inhibitors is difficult. In this review, we discuss the pathway of cMET, its clinical significance and the different diagnostic assays that are currently used, such as immunohistochemy (IHC), fluorescence in situ hybridization (FISH), the H-score and next-generation sequencing (NGS). Next, we discuss all the current data on cMET inhibitors in gastric cancer. Since the data on cMET inhibitors are very heterogenous, it is difficult to provide a general consensus on the outcome, as inclusion criteria differ between trials. Diagnosing cMET-driven gastric tumors is difficult, and potentially the only accurate determination of cMET overexpression/amplification may be next-generation sequencing (NGS).
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14
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Wu S, Xu P, Zhang F. Advances in targeted therapy for gastric cancer based on tumor driver genes. Zhejiang Da Xue Xue Bao Yi Xue Ban 2023; 53:73-83. [PMID: 38413217 PMCID: PMC10938109 DOI: 10.3724/zdxbyxb-2023-0522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Accepted: 01/23/2024] [Indexed: 02/29/2024]
Abstract
As the understanding of the pathogenic mechanisms of gastric cancer deepens and the identification of gastric cancer driver genes advances, drugs targeting gastric cancer driver genes have been applied in clinical practice. Among them, trastuzumab, as the first targeted drug for gastric cancer, effectively inhibits the proliferation and metastasis of tumor cells by targeting overexpressed human epidermal growth factor receptor 2 (HER2). Trastuzumab has become the standard treatment for HER2-positive gastric cancer patients. Ramucirumab, on the other hand, inhibits tumor angiogenesis by targeting vascular endothelial growth factor receptor 2 (VEGFR2) and has been used as second-line therapy for advanced gastric cancer patients. In addition, bemarituzumab targets overexpressed fibroblast growth factor receptor 2 (FGFR2), while zolbetuximab targets overexpressed claudin 18.2 (CLDN18.2), significantly extending progression-free survival and overall survival in patients with gastric cancer in clinical trials. This article reviews the roles of tumor driver genes in the progression of gastric cancer, and the treatment strategies for gastric cancer primarily based on targeting HER2, VEGF, FGFR2, CLDN18.2 and MET. This provides a reference for clinical application of targeted therapy for gastric cancer.
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Affiliation(s)
- Shiying Wu
- College of Food Science and Biotechnology, Zhejiang Gongshang University, Hangzhou 310018, China.
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
| | - Pinglong Xu
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
- Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
- Cancer Center, Zhejiang University, Hangzhou 310058, China.
| | - Fei Zhang
- Key Laboratory of Biosystems Homeostasis and Protection, Ministry of Education, Zhejiang Provincial Key Laboratory for Cancer Molecular Cell Biology, Zhejiang University, Hangzhou 310058, China.
- Institute of Intelligent Medicine, Hangzhou Global Scientific and Technological Innovation Center, Zhejiang University, Hangzhou 311200, China.
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15
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Chen JJ, Jin JM, Gu WJ, Zhao Z, Yuan H, Zhou YD, Nagle DG, Xi QL, Zhang XM, Sun QY, Wu Y, Zhang WD, Luan X. Crizotinib-based proteolysis targeting chimera suppresses gastric cancer by promoting MET degradation. Cancer Sci 2023; 114:1958-1971. [PMID: 36692137 PMCID: PMC10154821 DOI: 10.1111/cas.15733] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 01/14/2023] [Accepted: 01/17/2023] [Indexed: 01/25/2023] Open
Abstract
As one of the common malignant cancer types, gastric cancer (GC) is known for late-stage diagnosis and poor prognosis. Overexpression of the receptor tyrosine kinase MET is associated with poor prognosis among patients with advanced stage GC. However, no MET inhibitor has been used for GC treatment. Like other tyrosine kinase inhibitors that fit the "occupancy-driven" model, current MET inhibitors are prone to acquired resistance. The emerging proteolysis targeting chimera (PROTAC) strategy could overcome such limitations through direct degradation of the target proteins. In this study, we successfully transformed the MET-targeted inhibitor crizotinib into a series of PROTACs, recruiting cereblon/cullin 4A E3 ubiquitin ligase to degrade the MET proteins. The optimized lead PROTAC (PRO-6 E) effectively eliminated MET proteins in vitro and in vivo, inhibiting proliferation and motility of MET-positive GC cells. In the MKN-45 xenograft model, PRO-6 E showed pronounced antitumor efficacy with a well-tolerated dosage regimen. These results validated PRO-6 E as the first oral PROTAC for MET-dependent GC.
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Affiliation(s)
- Jin-Jiao Chen
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Jin-Mei Jin
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wen-Jie Gu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zeng Zhao
- School of Pharmacy, Shanghai Jiao Tong University, Shanghai, China.,State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, China
| | - Hu Yuan
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yu-Dong Zhou
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of Chemistry and Biochemistry, College of Liberal Arts, University of Mississippi, Boston, Massachusetts, USA
| | - Dale G Nagle
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China.,Department of BioMolecular Sciences and Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, Boston, Massachusetts, USA
| | - Qiu-Lei Xi
- Department of General Surgery, Zhongshan Hospital Affiliated to Fudan University, Shanghai, China
| | - Xue-Mei Zhang
- Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China
| | - Qing-Yan Sun
- State Key Laboratory of New Drug and Pharmaceutical Process, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, China
| | - Ye Wu
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Wei-Dong Zhang
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Xin Luan
- Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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16
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Phase I Study Evaluating Glesatinib (MGCD265), An Inhibitor of MET and AXL, in Patients with Non-small Cell Lung Cancer and Other Advanced Solid Tumors. Target Oncol 2023; 18:105-118. [PMID: 36459255 DOI: 10.1007/s11523-022-00931-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/31/2022] [Indexed: 12/05/2022]
Abstract
BACKGROUND Heightened signaling by mesenchymal epithelial transition factor (MET) is implicated in tumorigenesis. Glesatinib is an investigational, oral inhibitor of MET and AXL. OBJECTIVE This phase I study determined the maximum tolerated dose (MTD), recommended phase II dose (RP2D), and safety profile of glesatinib in patients with advanced or unresectable solid tumors. Antitumor activity and pharmacokinetics (PK) were secondary objectives. PATIENTS AND METHODS Four formulations of glesatinib glycolate salt (capsule, unmicronized, micronized, and micronized version 2 [V2] tablets) and two free-base formulations (free-base suspension [FBS] capsule and spray-dried dispersion [SDD] tablet), developed to enhance drug exposure and optimize manufacturing processes, were evaluated in patients with genetically unselected advanced/unresectable solid tumors. MTD, based on dose-limiting toxicities (DLTs) observed during the first 21-day treatment cycle, was further evaluated in dose-expansion cohorts comprising patients with overexpression of MET and/or AXL, MET/AXL amplification, MET-activating mutations, or MET/AXL rearrangements for confirmation as the RP2D. RESULTS Glesatinib was evaluated across 27 dose-escalation cohorts (n = 108). Due to suboptimal exposure with glesatinib glycolate salt formulations in the initial cohorts, investigations subsequently focused on the FBS capsule and SDD tablet; for these formulations, MTD was identified as 1050 mg twice daily and 750 mg twice daily, respectively. An additional 71 patients received glesatinib in the FBS and SDD dose-expansion cohorts. At MTDs, the most frequent treatment-related adverse events were diarrhea (FBS, 83.3%; SDD, 75.0%), nausea (57.1%, 30.6%), vomiting (45.2%, 25.0%), increased alanine aminotransferase (45.2%, 30.6%), and increased aspartate aminotransferase (47.6%, 27.8%). Exploratory pharmacodynamic analyses indicated target engagement and inhibition of MET by glesatinib. Antitumor activity was observed with glesatinib FBS 1050 mg twice daily and SDD 750 mg twice daily in tumors harboring MET/AXL alteration or aberrant protein expression, particularly in patients with non--small cell lung cancer (NSCLC). In patients with NSCLC, the objective response rate was 25.9% in those with MET/AXL mutation or amplification and 30.0% in a subset with MET-activating mutations. All six partial responses occurred in patients with tumors carrying MET exon 14 deletion mutations. CONCLUSIONS The safety profile of single-agent glesatinib was acceptable. SDD 750 mg twice daily was selected as the preferred glesatinib formulation and dose based on clinical activity, safety, and PK data. Observations from this study led to initiation of a phase II study of glesatinib in patients with NSCLC stratified by type of MET alteration (NCT02544633). CLINICAL TRIALS REGISTRATION ClinicalTrials.gov NCT00697632; June 2008.
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17
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Wang C, Li J, Qu L, Tang X, Song X, Yang F, Chen X, Lin Q, Lin W, Zhou Y, Tu Z, Chen Y, Zhang Z, Lu X. Discovery of D6808, a Highly Selective and Potent Macrocyclic c-Met Inhibitor for Gastric Cancer Harboring MET Gene Alteration Treatment. J Med Chem 2022; 65:15140-15164. [DOI: 10.1021/acs.jmedchem.2c00981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Chaofan Wang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Jie Li
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Lingzhi Qu
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xia Tang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Xiaojuan Song
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Fang Yang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Xiaojuan Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Qianmeng Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Weibin Lin
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Yang Zhou
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - ZhengChao Tu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Zhang Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
| | - Xiaoyun Lu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, #855 Xingye Avenue, Guangzhou 510632, China
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18
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Yu W, Chen G, Yan J, Wang X, Zhu Y, Zhu L. Single-cell sequencing analysis reveals gastric cancer microenvironment cells respond vastly different to oxidative stress. J Transl Med 2022; 20:250. [PMID: 35659682 PMCID: PMC9164398 DOI: 10.1186/s12967-022-03411-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2021] [Accepted: 04/24/2022] [Indexed: 11/10/2022] Open
Abstract
Gastric cancer is a common type of gastrointestinal malignant tumor in China. The mechanism of the development and progression of gastric cancer remains the continuing research focus. The tumor microenvironment plays an important role in the development and progression of tumors. The present study used single-cell sequencing data to characterize the microenvironment of gastric cancer, investigate the effects of oxidative stress on gastric cancer microenvironmental cells through the comparison between cancer tissue and normal tissue, and identify the key genes associated with gastric cancer patients' survival. The results showed that compared with normal gastric tissue, gastric cancer tissue had a decreased oxidative stress response, weaker oxidative detoxification ability, and increased oxidative stress-induced cell death. In the different types of single cells of gastric cancer microenvironment, the oxidative stress response of T cell was increased, the ability of oxidative detoxification was enhanced, and the oxidative stress-induced cell death was exacerbate. Mucous cell showed the same trend as gastric cancer cells: decreased oxidative stress response, weak oxidative detoxification ability, and weakened oxidative stress-induced cell death. Moreover, TRIM62, MET, and HBA1, which were significantly associated with oxidative stress, may be biomarkers for the prognosis of gastric cancer. High expression of TRIM62 indicated a good prognosis, while MET and HBA1 indicated a poor prognosis, which will be confirmed by further clinical studies.
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Affiliation(s)
- Weihua Yu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China
| | - Guojun Chen
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China
| | - Jiafei Yan
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China
| | - Xianfa Wang
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China
| | - Yiping Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China
| | - Linghua Zhu
- Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, 3 East Qingchun Road, Hangzhou, 310016, Zhejiang, China.
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19
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Bregni G, Beck B. Toward Targeted Therapies in Oesophageal Cancers: An Overview. Cancers (Basel) 2022; 14:1522. [PMID: 35326673 PMCID: PMC8946490 DOI: 10.3390/cancers14061522] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 03/10/2022] [Accepted: 03/14/2022] [Indexed: 12/04/2022] Open
Abstract
Oesophageal cancer is one of the leading causes of cancer-related death worldwide. Oesophageal cancer occurs as squamous cell carcinoma (ESCC) or adenocarcinoma (EAC). Prognosis for patients with either ESCC or EAC is poor, with less than 20% of patients surviving more than 5 years after diagnosis. A major progress has been made in the development of biomarker-driven targeted therapies against breast and lung cancers, as well as melanoma. However, precision oncology for patients with oesophageal cancer is still virtually non-existent. In this review, we outline the recent advances in oesophageal cancer profiling and clinical trials based on targeted therapies in this disease.
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Affiliation(s)
- Giacomo Bregni
- Institut Jules Bordet, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium;
| | - Benjamin Beck
- Welbio and FNRS Investigator at IRIBHM, Faculty of Medicine, Université Libre de Bruxelles (ULB), 1050 Brussels, Belgium
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20
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Choi S, Park S, Kim H, Kang SY, Ahn S, Kim KM. Gastric Cancer: Mechanisms, Biomarkers, and Therapeutic Approaches. Biomedicines 2022; 10:543. [PMID: 35327345 PMCID: PMC8945014 DOI: 10.3390/biomedicines10030543] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 02/22/2022] [Accepted: 02/22/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) remains one of the most common deadly malignancies worldwide. Recently, several targeted therapeutics for treating unresectable or metastatic GC have been developed. Comprehensive characterization of the molecular profile and of the tumor immune microenvironment of GC has allowed researchers to explore promising biomarkers for GC treatment and has enabled a new paradigm in precision-targeted immunotherapy. In this article, we review established and promising new biomarkers relevant in GC, with a focus on their clinical implications, diagnostic methods, and the efficacy of targeted agents.
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Affiliation(s)
- Sangjoon Choi
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
| | - Sujin Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
| | - Hyunjin Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
| | - So Young Kang
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
| | - Soomin Ahn
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
| | - Kyoung-Mee Kim
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Korea; (S.C.); (S.P.); (H.K.); (S.Y.K.); (S.A.)
- Center of Companion Diagnostics, Samsung Medical Center, Seoul 06351, Korea
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21
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Targeting HGF/c-Met Axis Decreases Circulating Regulatory T Cells Accumulation in Gastric Cancer Patients. Cancers (Basel) 2021; 13:cancers13215562. [PMID: 34771724 PMCID: PMC8583551 DOI: 10.3390/cancers13215562] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2021] [Revised: 10/30/2021] [Accepted: 11/02/2021] [Indexed: 01/02/2023] Open
Abstract
Simple Summary Restoring an effective immune response is the key goal of immunotherapy. One of the major mechanisms of tumor-induced immunosuppression is regulatory T cells (Treg) accumulation. In this study, using in vitro and in vivo analysis, we assessed the impact of the HGF/c-Met pathway, involved notably in tumor angiogenesis, on Treg accumulation in patients with gastric cancer. First, we reported that c-Met is expressed on circulating monocytes of gastric cancer patients and this expression seems to be associated with the worst outcome. Secondly, during in vitro cultures, c-Met+ monocytes differentiate into dendritic cells with tolerogenic properties able to induce the proliferation of Treg. Finally, rilotumumab, an anti-HGF antibody, decreases the percentage of circulating Treg in gastric cancer patients. Using HGF/c-Met inhibitors to partially reverse immunosuppression could lead to the development of new treatment associations, for example with immune checkpoint blockers. Abstract Elucidating mechanisms involved in tumor-induced immunosuppression is of great interest since it could help to improve cancer immunotherapy efficacy. Here we show that Hepatocyte Growth Factor (HGF), a pro-tumoral and proangiogenic factor, and its receptor c-Met are involved in regulatory T cells (Treg) accumulation in the peripheral blood of gastric cancer (GC) patients. We observed that c-Met is expressed on circulating monocytes from GC patients. The elevated expression on monocytes is associated with clinical parameters linked to an aggressive disease phenotype and correlates with a worse prognosis. Monocyte-derived dendritic cells from GC patients differentiated in the presence of HGF adopt a regulatory phenotype with a lower expression of co-stimulatory molecules, impaired maturation capacities, and an increased ability to produce interleukin-10 and to induce Treg differentiation in vitro. In the MEGA-ACCORD20-PRODIGE17 trial, GC patients received an anti-HGF antibody treatment (rilotumumab), which had been described to have an anti-angiogenic activity by decreasing proliferation of endothelial cells and tube formation. Rilotumumab decreased circulating Treg in GC patients. Thus, we identified that HGF indirectly triggers Treg accumulation via c-Met-expressing monocytes in the peripheral blood of GC patients. Our study provides arguments for potential alternative use of HGF/c-Met targeted therapies based on their immunomodulatory properties which could lead to the development of new therapeutic associations in cancer patients, for example with immune checkpoint inhibitors.
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22
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Molecular Targets for Gastric Cancer Treatment and Future Perspectives from a Clinical and Translational Point of View. Cancers (Basel) 2021; 13:cancers13205216. [PMID: 34680363 PMCID: PMC8533881 DOI: 10.3390/cancers13205216] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Gastric cancer is a leading cause of cancer death worldwide. Systemic treatment comprising chemotherapy and targeted therapy is the standard of care in advanced/metastatic gastric cancer. Comprehensive molecular characterization of gastric adenocarcinomas by the TCGA Consortium and ACRG has resulted in the definition of distinct molecular subtypes. These efforts have in parallel built a basis for the development of novel molecularly stratified treatment approaches. Based on this molecular characterization, an increasing number of specific genomic alterations can potentially serve as treatment targets. Consequently, the development of promising compounds is ongoing. In this review, key molecular alterations in gastric and gastroesophageal junction cancers will be addressed. Finally, the current status of the translation of targeted therapy towards clinical applications will be reviewed.
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Li J, Li Z, Ding Y, Xu Y, Zhu X, Cao N, Huang C, Qin M, Liu F, Zhao A. TP53 mutation and MET amplification in circulating tumor DNA analysis predict disease progression in patients with advanced gastric cancer. PeerJ 2021; 9:e11146. [PMID: 33959414 PMCID: PMC8054733 DOI: 10.7717/peerj.11146] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 03/03/2021] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) is a heterogeneous disease that encompasses various molecular subtypes. The molecular mutation characteristics of circulating tumor DNA (ctDNA) in advanced gastric cancer (AGC), especially the clinical utility of TP53 mutation and MET amplification in ctDNA need to be further explored. Objectives The aim of this study was mainly to assess the clinical utility of TP53 mutation and MET amplification in ctDNA as biomarkers for monitoring disease progression of AGC. Patients and Methods We used multigene NGS-panel technology to study the characteristics of ctDNA gene mutations and screen the key mutant genes in AGC patients. The Kaplan-Meier method was used to calculate the survival probability and log-rank test was used to compare the survival curves of TP53 mutation and MET amplification in ctDNA of AGC patients. The survival time was set from the blood test time to the follow-up time to observe the relationship between the monitoring index and tumor prognosis. Results We performed mutation detection on ctDNA in 23 patients with AGC and identified the top 20 mutant genes. The five most frequently mutated genes were TP53 (55%), EGFR (20%), ERBB2 (20%), MET (15%) and APC (10%). TP53 was the most common mutated gene (55%) and MET had a higher frequency of mutations (15%) in our study. Kaplan-Meier analysis showed that patients with TP53 mutant in ctDNA had shorter overall survival (OS) than these with TP53 wild (P < 0.001). The Allele frequency (AF) of TP53 mutations in patient number 1 was higher in the second time (0.94%) than in the first time (0.36%); the AF of TP53 mutations in patient number 16 was from scratch (0∼0.26%). In addition, the AF of TP53 mutations in patients who survive was relatively low (P = 0.047). Simultaneously, Kaplan-Meier analysis showed that patients with MET amplification also had shorter OS than these with MET without amplification (P < 0.001). Conclusion TP53 and MET are the two common frequently mutant genes in ctDNA of AGC patients.TP53 mutation and MET amplification in ctDNA could predict disease progression of AGC patients.
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Affiliation(s)
- Jia Li
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China.,Department of Integrated Chinese and Western Medicine, Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou, Henan, China
| | - Zhaoyan Li
- Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Yajie Ding
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Yan Xu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Xiaohong Zhu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Nida Cao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Chen Huang
- Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengmeng Qin
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Feng Liu
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
| | - Aiguang Zhao
- Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine (TCM), Shanghai, China
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24
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Chen C, Gu YM, Zhang F, Zhang ZC, Zhang YT, He YD, Wang L, Zhou N, Tang FT, Liu HJ, Li YM. Construction of PD1/CD28 chimeric-switch receptor enhances anti-tumor ability of c-Met CAR-T in gastric cancer. Oncoimmunology 2021; 10:1901434. [PMID: 33854821 PMCID: PMC8018404 DOI: 10.1080/2162402x.2021.1901434] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Chimeric antigen receptor (CAR) T cell is a promising method in cancer immunotherapy but faces many challenges in solid tumors. One of the major problems was immunosuppression caused by PD-1. In our study, the expression of c-Met in GC was analyzed from TCGA datasets, GC tissues, and cell lines. The c-Met CAR was a second-generation CAR with 4–1BB, cMet-PD1/CD28 CAR was c-Met CAR adding PD1/CD28 chimeric-switch receptor (CSR). In vitro, we measured the changes of different subgroups, phenotypes and PD-1 expression in CAR-T cells. We detected the secretion levels of different cytokines and the killing ability of CAR-Ts. In vivo, we established a xenograft GC model and observed the anti-tumor effect and off-target toxicity of different CAR-Ts. We find that the expression of c-Met was increased in GC. CD3+CD8+ T cells and CD62L+CCR7+ central memory T cells (TCM) were increased in two CAR-Ts. The stimulation of target cells could promote the expression of PD-1 in c-Met CAR-T. Compared with Mock T, the secretion of cytokines as IFN-γ, TNF-α, IL-6, IL-10 secreted by two CAR-Ts was increased, and the killing ability to c-Met positive GC cells was enhanced. The PD1/CD28 CSR could further enhance the killing ability, especially the long-term anti-tumor effect of c-Met CAR-T, and reduce the release level of IL-6. CAR-Ts target c-Met had no obvious off-target toxicity to normal organs. Thus, the PD1/CD28 CSR could further enhance the anti-tumor ability of c-Met CAR-T, and provides a promising design strategy to improve the efficacy of CAR-T in GC.
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Affiliation(s)
- Cong Chen
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China.,Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yan-Mei Gu
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Fan Zhang
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Zheng-Chao Zhang
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Ya-Ting Zhang
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Yi-Di He
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Ling Wang
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Ning Zhou
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Fu-Tian Tang
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China
| | - Hong-Jian Liu
- Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yu-Min Li
- Lanzhou University Second Hospital, the Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, Gansu, China
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25
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Jørgensen JT, Mollerup J, Yang H, Go N, Nielsen KB. MET deletion is a frequent event in gastric/gastroesophageal junction/esophageal cancer: a cross-sectional analysis of gene status and signal distribution in 1,580 patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:225. [PMID: 33708852 PMCID: PMC7940901 DOI: 10.21037/atm-20-4081] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Accepted: 11/01/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND MET gene aberrations are found in several human cancers including gastric, ovarian and lung. In a large multinational cohort of patients with gastric/gastroesophageal junction/esophageal (G/GEJ/E) adenocarcinoma we assessed the MET status with respect to amplification and deletion and correlate the results with the phenotypical gene signal distribution pattern. METHODS Tissue specimens from 1,580 patients were analyzed using a novel fluorescence in situ hybridization (FISH) assay employing a MET/CEN-7 IQFISH Probe Mix. MET amplification and deletions were defined as a MET/CEN-7 ratio ≥2.0 and a MET/CEN-7 ratio <0.8, respectively. Furthermore, the link between the MET gene status and the phenotypical signal distribution was investigated. RESULTS The prevalence of MET amplification and deletions was found to be 7.2% and 8.7%, respectively. Significant differences were observed with regard to geographic regions and sex. The Asian population had the highest percentage of MET amplification (9.4%) and the lowest percentage of deletions (3.2%). MET deletions was found more frequently among males (10.1%) compared to females (5.3%) and in esophagus (17.6%) compared to the stomach (5.7%). More than 50% of the patients who harbored MET gene amplification had a heterogeneous distribution of the FISH signals. Patients with a focal signal distribution were solely to be found among the MET amplified population. MET deletion were mainly observed in the group of patients with a homogenous signal distribution. CONCLUSIONS The screening data from this cross-sectional study showed that MET deletion and amplification are frequent events in G/GEJ/E cancer, which are linked to different phenotypical signal distribution patterns. The role of MET deletion in relation to tumor development is not fully understood but it is likely to play a role in the oncogenic transformation of the cells.
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Affiliation(s)
| | - Jens Mollerup
- Pathology Division, Agilent Technologies, Glostrup, Denmark
| | - Hui Yang
- Medical Sciences, Amgen Inc., Thousand Oaks, USA
| | - Ning Go
- Medical Sciences, Amgen Inc., Thousand Oaks, USA
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26
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Pharmaceutical strategies in the emerging era of antibody-based biotherapeutics for the treatment of cancers overexpressing MET receptor tyrosine kinase. Drug Discov Today 2020; 26:106-121. [PMID: 33171292 DOI: 10.1016/j.drudis.2020.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/23/2020] [Accepted: 11/03/2020] [Indexed: 12/26/2022]
Abstract
Pharmaceutical innovation in the development of novel antibody-based biotherapeutics with increased therapeutic indexes makes MET-targeted cancer therapy a clinical reality.
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27
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Shao Z, Pan H, Tu S, Zhang J, Yan S, Shao A. HGF/c-Met Axis: The Advanced Development in Digestive System Cancer. Front Cell Dev Biol 2020; 8:801. [PMID: 33195182 PMCID: PMC7649216 DOI: 10.3389/fcell.2020.00801] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 07/28/2020] [Indexed: 12/22/2022] Open
Abstract
Numerous studies have indicated that abnormal activation of the HGF/c-Met signaling pathway can lead to cell proliferation, invasiveness, and metastasis of cancers of the digestive system. Moreover, overexpression of c-Met has been implicated in poor prognosis of patients with these forms of cancer, suggesting the possibility for HGF/c-Met axis as a potential therapeutic target. Despite the large number of clinical and preclinical trials worldwide, no significant positive success in the use of anti-HGF/c-Met treatments on cancers of the digestive system has been achieved. In this review, we summarize advanced development of clinical research on HGF/c-Met antibody and small-molecule c-Met inhibitors of cancers of the digestive system and provide a possible direction for future research.
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Affiliation(s)
- Zhiwei Shao
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Haoqi Pan
- Department of General Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Tu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jingying Zhang
- Department of General Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Sheng Yan
- Department of Hepatobiliary and Pancreatic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Anwen Shao
- Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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28
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Yao HP, Hudson R, Wang MH. Progress and challenge in development of biotherapeutics targeting MET receptor for treatment of advanced cancer. Biochim Biophys Acta Rev Cancer 2020; 1874:188425. [PMID: 32961258 DOI: 10.1016/j.bbcan.2020.188425] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Revised: 09/15/2020] [Accepted: 09/15/2020] [Indexed: 12/15/2022]
Abstract
Advanced epithelial cancers such as gastric, lung, and pancreatic tumors are featured by invasive proliferation, distant metastasis, acquired chemoresistance, and tumorigenic stemness. For the last decade, molecular-targeted therapies using therapeutic antibodies, small molecule kinase inhibitors and immune-checkpoint blockades have been applied for these diseases with significant clinical benefits. Nevertheless, there is still a large gap to achieve curative outcomes. MET (mesenchymal-epithelial transition protein), a receptor tyrosine kinase, is a tumorigenic determinant that regulates epithelial cancer initiation, progression, and malignancy. Increased MET expression also has prognostic value for cancer progression and patient survival. These features provide the rationale to target MET for cancer treatment. In this review, we discuss the importance of MET in epithelial tumorigenesis and the development of antibody-based biotherapeutics, including bispecific antibodies and antibody-drug conjugates, for clinical application. The findings from both preclinical and clinical studies highlight the potential of MET-targeted biotherapeutics for cancer therapy in the future.
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Affiliation(s)
- Hang-Ping Yao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
| | - Rachel Hudson
- Cancer Biology Research Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA
| | - Ming-Hai Wang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; National Clinical Research Center for Infectious Diseases, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China; Cancer Biology Research Center, Texas Tech University Health Sciences Center, Amarillo, TX, USA; Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX, USA.
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29
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Zhu C, Shi H, Wu M, Wei X. A dual MET/AXL small-molecule inhibitor exerts efficacy against gastric carcinoma through killing cancer cells as well as modulating tumor microenvironment. MedComm (Beijing) 2020; 1:103-118. [PMID: 34766112 PMCID: PMC8489669 DOI: 10.1002/mco2.11] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 05/26/2020] [Accepted: 05/26/2020] [Indexed: 02/05/2023] Open
Abstract
The receptor tyrosine kinases MET and AXL have been implicated in tumorigenesis and aggressiveness of multiple malignancies. We performed this study to evaluate the antitumor impact of LY2801653, a dual MET and AXL inhibitor on gastric cancer and to elucidate the underlying mechanisms. In the present study, tissue microarrays containing gastric cancer tissues were stained with MET and AXL antibodies, which showed the prognostic values of MET and AXL. Administration of LY2801653 inhibited cell proliferation, migration, epithelial‐mesenchymal transition, induced apoptosis, and cell cycle arrest. Xenograft mouse models showed suppressed cell proliferation of tumors in high MET and AXL expression cells. LY2801653 also inhibited the growth of MET and AXL‐independent cells at higher but clinically relevant doses through decreased angiogenesis and M2 macrophages in the tumor microenvironment. In conclusion, our study provides evidence for MET and AXL as prognostic biomarkers and potential therapeutic targets in gastric cancer. The dual MET/AXL inhibitor LY2801653 represents a promising therapeutic strategy for the treatment of patients with gastric carcinoma.
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Affiliation(s)
- Chenjing Zhu
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China.,Department of Radiation Oncology Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University Nanjing Jiangsu China
| | - Huashan Shi
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
| | - Min Wu
- Department of Biomedical Sciences School of Medicine and Health Sciences University of North Dakota Grand Forks North Dakota USA
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Drug Target State Key Laboratory of Biotherapy and Cancer Center National Clinical Research Center for Geriatrics West China Hospital Sichuan University Chengdu Sichuan China
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30
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Strickler JH, LoRusso P, Salgia R, Kang YK, Yen CJ, Lin CC, Ansell P, Motwani M, Wong S, Yue H, Wang L, Reilly E, Afar D, Naumovski L, Ramanathan RK. Phase I Dose-Escalation and -Expansion Study of Telisotuzumab (ABT-700), an Anti-c-Met Antibody, in Patients with Advanced Solid Tumors. Mol Cancer Ther 2020; 19:1210-1217. [PMID: 32127466 DOI: 10.1158/1535-7163.mct-19-0529] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 10/25/2019] [Accepted: 02/28/2020] [Indexed: 11/16/2022]
Abstract
This first-in-human phase I study evaluated the pharmacokinetics, safety, and preliminary efficacy of telisotuzumab, formerly called ABT-700, an antagonistic antibody directed against c-Met. For dose escalation (3+3 design), 3 to 6 patients with advanced solid tumors were enrolled into four dose cohorts (5-25 mg/kg). In the dose-expansion phase, a subset of patients was prospectively selected for MET amplification (FISH screening). Patients received telisotuzumab intravenously on day 1 every 21 days. For dose expansion, 15 mg/kg was chosen as the dose on the basis of safety, pharmacokinetics, and other data from the escalation cohorts. Forty-five patients were enrolled and received at least one dose of telisotuzumab (dose escalation, n = 15; dose expansion, n = 30). Telisotuzumab showed a linear pharmacokinetics profile; peak plasma concentration was proportional to dose level. There were no acute infusion reactions and no dose-limiting toxicities were observed. The most common treatment-related adverse events included hypoalbuminemia (n = 9, 20.0%) and fatigue (n = 5, 11.1%). By Response Evaluation Criteria In Solid Tumors (RECIST), 4 of 10 (40.0%) patients with MET-amplified tumors had confirmed partial response in target lesions (one ovarian, two gastric, and one esophageal), two (20.0%) had stable disease, three (30.0%) had progressive disease; one patient was unable to be evaluated. Among patients with nonamplified tumors (n = 35), no objective responses were observed; however, 11 patients had stable disease per RECIST criteria. In conclusion, telisotuzumab has an acceptable safety profile with clinical activity observed in patients with MET-amplified advanced solid tumors.
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Affiliation(s)
| | - Patricia LoRusso
- Yale University School of Medicine, Yale Cancer Center, New Haven, Connecticut
| | | | - Yoon-Koo Kang
- Asan Medical Center, University of Ulsan, Seoul, South Korea
| | - Chia Jui Yen
- National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan City, Taiwan
| | - Chia-Chi Lin
- National Taiwan University Hospital, Taipei, Taiwan
| | | | | | - Shekman Wong
- Oncology Early Development, AbbVie Inc., Redwood City, California
| | - Huibin Yue
- Oncology Early Development, AbbVie Inc., Redwood City, California
| | - Lan Wang
- Oncology Early Development, AbbVie Inc., Redwood City, California
| | | | - Daniel Afar
- Oncology Early Development, AbbVie Inc., Redwood City, California
| | - Louie Naumovski
- Oncology Early Development, AbbVie Inc., Redwood City, California
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31
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Lee PC, Chen ST, Kuo TC, Lin TC, Lin MC, Huang J, Hung JS, Hsu CL, Juan HF, Lee PH, Huang MC. C1GALT1 is associated with poor survival and promotes soluble Ephrin A1-mediated cell migration through activation of EPHA2 in gastric cancer. Oncogene 2020; 39:2724-2740. [PMID: 32005975 PMCID: PMC7098884 DOI: 10.1038/s41388-020-1178-7] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 01/13/2020] [Accepted: 01/21/2020] [Indexed: 11/09/2022]
Abstract
C1GALT1 controls the crucial step of GalNAc-type O-glycosylation and is associated with both physiologic and pathologic conditions, including cancers. EPH receptors comprise the largest family of receptor tyrosine kinases (RTKs) and modulate a diverse range of developmental processes and human diseases. However, the role of C1GALT1 in the signaling of EPH receptors remains largely overlooked. Here, we showed that C1GALT1 high expression in gastric adenocarcinomas correlated with adverse clinicopathologic features and is an independent prognostic factor for poor overall survival. Silencing or loss of C1GALT1 inhibited cell viability, migration, invasion, tumor growth and metastasis, as well as increased apoptosis and cytotoxicity of 5-fluorouracil in AGS and MKN45 cells. Phospho-RTK array and western blot analysis showed that C1GALT1 depletion suppressed tyrosine phosphorylation of EPHA2 induced by soluble Ephrin A1-Fc. O-glycans on EPHA2 were modified by C1GALT1 and both S277A and T429A mutants, which are O-glycosites on EPHA2, dramatically enhanced phosphorylation of Y588, suggesting that not only overall O-glycan structures but also site-specific O-glycosylation can regulate EPHA2 activity. Furthermore, depletion of C1GALT1 decreased Ephrin A1-Fc induced migration and reduced Ephrin A1 binding to cell surfaces. The effects of C1GALT1 knockdown or knockout on cell invasiveness in vitro and in vivo were phenocopied by EPHA2 knockdown in gastric cancer cells. These results suggest that C1GALT1 promotes phosphorylation of EPHA2 and enhances soluble Ephrin A1-mediated migration primarily by modifying EPHA2 O-glycosylation. Our study highlights the importance of GalNAc-type O-glycosylation in EPH receptor-regulated diseases and identifies C1GALT1 as a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Po-Chu Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.,Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Syue-Ting Chen
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Ting-Chun Kuo
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.,Department of Traumatology, National Taiwan University Hospital, Taipei, Taiwan.,Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Tzu-Chi Lin
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Mei-Chun Lin
- Department of Otolaryngology, National Taiwan University Hospital, Taipei, Taiwan
| | - John Huang
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Ji-Shiang Hung
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan
| | - Chia-Lang Hsu
- Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan
| | - Hsueh-Fen Juan
- Department of Life Science, National Taiwan University, Taipei, Taiwan
| | - Po-Huang Lee
- Department of Surgery, National Taiwan University Hospital, Taipei, Taiwan.,Department of Surgery, E-DA Hospital, Kaohsiung City, Taiwan
| | - Min-Chuan Huang
- Graduate Institute of Anatomy and Cell Biology, College of Medicine, National Taiwan University, Taipei, Taiwan.
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32
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Moosavi F, Giovannetti E, Saso L, Firuzi O. HGF/MET pathway aberrations as diagnostic, prognostic, and predictive biomarkers in human cancers. Crit Rev Clin Lab Sci 2019; 56:533-566. [PMID: 31512514 DOI: 10.1080/10408363.2019.1653821] [Citation(s) in RCA: 123] [Impact Index Per Article: 20.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2019] [Revised: 07/13/2019] [Accepted: 08/05/2019] [Indexed: 12/24/2022]
Abstract
Cancer is a major cause of death worldwide. MET tyrosine kinase receptor [MET, c-MET, hepatocyte growth factor (HGF) receptor] pathway activation is associated with the appearance of several hallmarks of cancer. The HGF/MET pathway has emerged as an important actionable target across many solid tumors; therefore, biomarker discovery becomes essential in order to guide clinical intervention and patient stratification with the aim of moving towards personalized medicine. The focus of this review is on how the aberrant activation of the HGF/MET pathway in tumor tissue or the circulation can provide diagnostic and prognostic biomarkers and predictive biomarkers of drug response. Many meta-analyses have shown that aberrant activation of the MET pathway in tumor tissue, including MET gene overexpression, gene amplification, exon 14 skipping and other activating mutations, is almost invariably associated with shorter survival and poor prognosis. Most meta-analyses have been performed in non-small cell lung cancer (NSCLC), breast, head and neck cancers as well as colorectal, gastric, pancreatic and other gastrointestinal cancers. Furthermore, several studies have shown the predictive value of MET biomarkers in the identification of patients who gain the most benefit from HGF/MET targeted therapies administered as single or combination therapies. The highest predictive values have been observed for response to foretinib and savolitinib in renal cancer, as well as tivantinib in NSCLC and colorectal cancer. However, some studies, especially those based on MET expression, have failed to show much value in these stratifications. This may be rooted in lack of standardization of methodologies, in particular in scoring systems applied in immunohistochemistry determinations or absence of oncogenic addiction of cancer cells to the MET pathway, despite detection of overexpression. Measurements of amplification and mutation aberrations are less likely to suffer from these pitfalls. Increased levels of MET soluble ectodomain (sMET) in circulation have also been associated with poor prognosis; however, the evidence is not as strong as it is with tissue-based biomarkers. As a diagnostic biomarker, sMET has shown its value in distinguishing cancer patients from healthy individuals in prostate and bladder cancers and in melanoma. On the other hand, increased circulating HGF has also been presented as a valuable prognostic and diagnostic biomarker in many cancers; however, there is controversy on the predictive value of HGF as a biomarker. Other biomarkers such as circulating tumor DNA (ctDNA) and tumor HGF levels have also been briefly covered. In conclusion, HGF/MET aberrations can provide valuable diagnostic, prognostic and predictive biomarkers and represent vital assets for personalized cancer therapy.
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Affiliation(s)
- Fatemeh Moosavi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
| | - Elisa Giovannetti
- Department of Medical Oncology, Cancer Center Amsterdam, Amsterdam UMC, VU University Medical Center (VUmc) , Amsterdam , The Netherlands
- Cancer Pharmacology Lab, AIRC Start Up Unit, Fondazione Pisana per la Scienza Onlus , Pisa , Italy
| | - Luciano Saso
- Department of Physiology and Pharmacology, "Vittorio Erspamer," Sapienza University , Rome , Italy
| | - Omidreza Firuzi
- Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences , Shiraz , Iran
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33
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Zhou C, Zhong X, Song Y, Shi J, Wu Z, Guo Z, Sun J, Wang Z. Prognostic Biomarkers for Gastric Cancer: An Umbrella Review of the Evidence. Front Oncol 2019; 9:1321. [PMID: 31850212 PMCID: PMC6895018 DOI: 10.3389/fonc.2019.01321] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 11/12/2019] [Indexed: 12/14/2022] Open
Abstract
Introduction: Biomarkers are biological molecules entirely or partially participating in cancerous processes that function as measurable indicators of abnormal changes in the human body microenvironment. Aiming to provide an overview of associations between prognostic biomarkers and gastric cancer (GC), we performed this umbrella review analyzing currently available meta-analyses and grading the evidence depending on the credibility of their associations. Methods: A systematic literature search was conducted by two independent investigators of the PubMed, Embase, Web of Science, and Cochrane Databases to identify meta-analyses investigating associations between prognostic biomarkers and GC. The strength of evidence for prognostic biomarkers for GC were categorized into four grades: strong, highly suggestive, suggestive, and weak. Results: Among 120 associations between prognostic biomarkers and GC survival outcomes, only one association, namely the association between platelet count and GC OS, was supported by strong evidence. Associations between FITC, CEA, NLR, foxp3+ Treg lymphocytes (both 1- and 3-year OS), CA 19-9, or VEGF and GC OS were supported by highly suggestive evidence. Four associations were considered suggestive and the remaining 108 associations were supported by weak or not suggestive evidence. Discussion: The association between platelet count and GC OS was supported by strong evidence. Associations between FITC, CEA, NLR, foxp3+ Treg lymphocytes (both 1- and 3-year OS), CA 19-9, or VEGF and GC OS were supported by highly suggestive evidence, however, the results should be interpreted cautiously due to inadequate methodological quality as deemed by AMSTAR 2.0.
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Affiliation(s)
- Cen Zhou
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Xi Zhong
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jinxin Shi
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhonghua Wu
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhexu Guo
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Jie Sun
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Zhenning Wang
- Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, Shenyang, China
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Xu H, Peng L, Shen M, Xia Y, Li Z, He N. Shiga-like toxin I exerts specific and potent anti-tumour efficacy against gastric cancer cell proliferation when driven by tumour-preferential Frizzled-7 promoter. Cell Prolif 2019; 52:e12607. [PMID: 30955216 PMCID: PMC6536451 DOI: 10.1111/cpr.12607] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2019] [Revised: 02/22/2019] [Accepted: 02/22/2019] [Indexed: 02/03/2023] Open
Abstract
OBJECTIVES Tumour-targeted gene therapy is a promising approach for effective control of gastric cancer cell proliferation. Our study aims to develop a cancer therapy which combines tumour-targeting promoters with cytotoxins. METHODS The expression of globotriaosylceramide (Gb3), which is a Shiga-like toxin I (Stx1) receptor, was verified in gastric cancer compared with normal stomach tissues as assessed by flow cytometry and immunohistochemical analysis. We therefore constructed the recombinant pFZD7-Stx1 plasmid vectors with tumour-preferential Frizzled-7 promoter and Stx1. pFZD7-Stx1 was used to treat gastric cancer in vitro and in vivo. The gastric cancer cell proliferation and tumour growth were identified after the transfection with the pFZD7-Stx1. RESULTS Globotriaosylceramide was obviously increased in gastric cancer compared with normal stomach. The gastric cancer cell proliferation and tumour growth decreased significantly after the transfection with the pFZD7-Stx1. CONCLUSION Frizzled-7 promoter is preferentially active, and Gb3 is abundant in gastric cancer cells. Frizzled-7 promoter and Stx1 may be used to determine a novel and relatively specific and potent gastric cancer therapeutic strategy.
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Affiliation(s)
- Hongpan Xu
- Department of Clinical LaboratoryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Lijun Peng
- Department of Clinical LaboratoryDrum Tower Clinical College of Nanjing Medical UniversityNanjingChina
| | - Mengjiao Shen
- Department of Clinical LaboratoryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Yanyan Xia
- Department of Clinical LaboratoryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Zhiyang Li
- Department of Clinical LaboratoryThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjingChina
| | - Nongyue He
- State Key Laboratory of BioelectronicsSoutheast UniversityNanjingChina
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Athauda A, Chau I. Do investigational MET inhibitors have potential for the treatment of gastric cancer? Expert Opin Investig Drugs 2019; 28:299-302. [PMID: 30768360 DOI: 10.1080/13543784.2019.1582641] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Affiliation(s)
- Avani Athauda
- a Gastrointestinal and Lymphoma Unit , The Royal Marsden Hospital NHS Foundation Trust , Sutton , Surrey , United Kingdom
| | - Ian Chau
- a Gastrointestinal and Lymphoma Unit , The Royal Marsden Hospital NHS Foundation Trust , Sutton , Surrey , United Kingdom
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Tirino G, Pompella L, Petrillo A, Laterza MM, Pappalardo A, Caterino M, Orditura M, Ciardiello F, Galizia G, De Vita F. What's New in Gastric Cancer: The Therapeutic Implications of Molecular Classifications and Future Perspectives. Int J Mol Sci 2018; 19:E2659. [PMID: 30205505 PMCID: PMC6165492 DOI: 10.3390/ijms19092659] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2018] [Revised: 09/03/2018] [Accepted: 09/05/2018] [Indexed: 02/05/2023] Open
Abstract
Despite some remarkable innovations and the advent of novel molecular classifications the prognosis of patients with advanced gastric cancer (GC) remains overall poor and current clinical application of new advances is disappointing. During the last years only Trastuzumab and Ramucirumab have been approved and currently used as standard of care targeted therapies, but the systemic management of advanced disease did not radically change in contrast with the high number of molecular drivers identified. The Cancer Genome Atlas (TCGA) and Asian Cancer Research Group (ACRG) classifications paved the way, also for GC, to that more contemporary therapeutic approach called "precision medicine" even if tumor heterogeneity and a complex genetic landscape still represent a strong barrier. The identification of specific cancer subgroups is also making possible a better selection of patients that are most likely to respond to immunotherapy. This review aims to critically overview the available molecular classifications summarizing the main druggable molecular drivers and their possible therapeutic implications also taking advantage of new technologies and acquisitions.
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Affiliation(s)
- Giuseppe Tirino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Luca Pompella
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Angelica Petrillo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Maria Maddalena Laterza
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Annalisa Pappalardo
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Marianna Caterino
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Michele Orditura
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Fortunato Ciardiello
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Gennaro Galizia
- Division of GI Tract Surgical Oncology, Department of Cardio-Thoracic and Respiratory Sciences, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
| | - Ferdinando De Vita
- Division of Medical Oncology, Department of Precision Medicine, School of Medicine, University of Campania "Luigi Vanvitelli", Via Pansini n.5, 80131 Naples, Italy.
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Abbas M, Faggian A, Sintali DN, Khan GJ, Naeem S, Shi M, Dingding C. Current and future biomarkers in gastric cancer. Biomed Pharmacother 2018; 103:1688-1700. [DOI: 10.1016/j.biopha.2018.04.178] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 04/24/2018] [Accepted: 04/24/2018] [Indexed: 02/06/2023] Open
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Noguchi K, Konno M, Eguchi H, Kawamoto K, Mukai R, Nishida N, Koseki J, Wada H, Akita H, Satoh T, Marubashi S, Nagano H, Doki Y, Mori M, Ishii H. c-Met affects gemcitabine resistance during carcinogenesis in a mouse model of pancreatic cancer. Oncol Lett 2018; 16:1892-1898. [PMID: 30008881 DOI: 10.3892/ol.2018.8793] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2015] [Accepted: 02/28/2018] [Indexed: 12/11/2022] Open
Abstract
Pancreatic adenocarcinoma is thought to develop from histologically identifiable intraductal lesions known as pancreatic intraepithelial neoplasias (PanINs), which exhibit similar morphological and genetic features to pancreatic ductal adenocarcinoma (PDAC). Therefore, a better understanding of the biological features underlying the progression of PanIN is essential to development more effective therapeutic interventions for PDAC. In recent years, numerous studies have reported that MET proto-oncogene receptor tyrosine kinase (c-MET) is a potential marker of pancreatic cancer stem cells (CSCs). CSCs have been revealed to initiate and propagate tumors in vitro and in vivo, and are associated with a chemoresistant phenotype. However, in vivo models using a xenograft approach are limited. In the present study, the morphological phenotype, molecular alteration and biological behavior of neoplasia in Pdx-1Cre/+, KrasLSL-G12D/+ and Metflox/flox and wild-type mice was analyzed. The results demonstrated that while oncogenic KrasLSL-G12D/+ increased PanIN initiation and significantly decreased survival rate compared with wild-type mice, no additive effect of c-Met receptor signaling on PanIN progression or prognosis was observed. Following gemcitabine administration, c-Met inhibition in Kras LSL-G12D/+ mice significantly decreased the total surface area of PanIN lesions and the number of anti-proliferation marker protein Ki-67 positive cells occupying PanIN lesions compared with Met+/+ mice. In conclusion, complete inhibition of the c-Met signaling pathway with chemotherapy may be useful for the treatment of pancreatic cancer.
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Affiliation(s)
- Kozo Noguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Ryouta Mukai
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Shigeru Marubashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan.,Department of Medical Data Science, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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Qian H, Appiah-Kubi K, Wang Y, Wu M, Tao Y, Wu Y, Chen Y. The clinical significance of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) in gastric cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2018; 127:15-28. [PMID: 29891108 DOI: 10.1016/j.critrevonc.2018.05.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Revised: 03/25/2018] [Accepted: 05/07/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The overexpression and mutation of platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are widespread in cancers and have been recognized as attractive oncologic targets with diverse therapeutic targets. Reports of the overexpression of genes, proteins and mutations of PDGFs/PDGFRs in gastric cancer and their associations with clinicopathological features, Western and Asian patients, as well as prognostic role have shown variable outcomes. This study sought to employ meta-analysis to evaluate PDGFs/PDGFRs status prognostic significance and their association with clinicopathological features of gastric cancer. METHOD A comprehensive search of PubMed database for studies that investigated the overexpression of mRNA/Protein and mutation of PDGFs/PDGFRs in gastric cancer of Western and Asian patients, their prognostic significance and association with clinicopathological characteristics in May, 2017 or earlier was carried out by two reviewers independently. Pooled odd ratios and hazard ratios at 95% confidence intervals were estimated and summarized using fixed-effect and random-effect Mantel-Haenszel models and Inverse Variance models in Review Manager software version 5.3. RESULTS Fourteen studies with 16 datasets of 1178 patients were included in meta-analysis. Fourteen studies of 1178 patients with 1446 cases and 7 studies of 1076 patients with 1280 cases were included in meta-analysis of clinicopathological and prognostic significance of high or positive PDGF/PDGFR status respectively. Odd ratio at 95% confidence intervals for different groups of analysis are as follows: males versus females(OR = 1.38, 95% CI: 1.04-1.83, POR = 0.03); ≥T2 stage versus T1 stage(OR = 2.06, 95% CI: 1.22-3.49, POR = 0.007); nodal metastasis versus no nodal metastasis(OR = 2.78, 95% CI: 1.48-5.22, POR = 0.002); TNM stage ≥II versus TNM stage I(OR = 3.55, 95% CI: 1.89-6.69, POR<0.0001). Subgroup analysis of the association of PDGF/PDGFR among Western patients(OR = 0.24 95% CI: 0.10-0.58, POR = 0.002) and association of PDGFs/PDGFRs gene mutation among gastric cancer patients(OR = 0.15, 95% CI: 0.05-0.45, POR = 0.0008) were significant. The association of PDGFs/PDGFRs in young and middle age versus elderly aged, undifferentiated versus well differentiated tumors, large tumor size group(>6 cm) versus small tumor size group(≤6 cm) were insignificant. Subgroup analysis of the association of PDGFs/PDGFRs among Western Asian patients; PDGF/PDGFR mRNA expression and protein expression among gastric cancer patients were insignificant. In addition, PDGF/PDGFR status among gastric cancer patients was insignificant in overall effect analysis PDGF/PDGFR status has shown to predict reduced overall survival(HR = 1.25, 95% CI: 0.49-3.22, PHR = 0.64) and relapse free survival(HR = 0.93, 95% CI: 0.36-2.41, PHR = 0.88) insignificantly. Also, overall prognostic effect analysis(HR = 1.07, 95% CI: 0.58-1.96, PHR = 0.84) was insignificant. CONCLUSION PDGFs/PDGFRs status amongst gastric cancer patients plays a key role in clinical variables and nodal metastasis. These insights might be helpful in providing guidelines for diagnosis, molecular target therapy, and prognosis of gastric cancer.
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Affiliation(s)
- Hai Qian
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Kwaku Appiah-Kubi
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China; Department of Applied Biology, University for Development Studies, Navrongo, Ghana.
| | - Ying Wang
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Min Wu
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Yan Tao
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Yan Wu
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China
| | - Yongchang Chen
- Department of Physiology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, 212013, People's Republic of China.
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Neves Filho EHC, Pires APB, de Sant'Ana RO, Rabenhorst SHB, Hirth CG, da Cunha MDPSS. The association among HER2, MET and FOXP3 expression and tumor regression grading in gastric adenocarcinoma. APMIS 2018; 126:389-395. [PMID: 29696715 DOI: 10.1111/apm.12840] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 03/06/2018] [Indexed: 12/13/2022]
Abstract
Although the introduction of the perioperative chemotherapy on the management of gastric cancer has improved patients survival, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Thus, this study evaluated the tumor regression grading (TRG) in a series of post-treatment gastric tumors and its associations with HER2, MET, and FOXP3 expression. Material of 54 gastric cancer samples was available for TRG evaluation and immunohistochemistry. We found that total and subtotal pathologic response were significantly associated to the intestinal subtype (p = 0.04) and that well-differentiated tumors were significantly correlated with total or partial response (p = 0.019). Although not associated with the TRG, FOXP3 expression in gastric tumors was associated to poorly differentiated tumors (p = 0.03), to the diffuse and mixed subtypes together (p = 0.04) and to the presence of vascular infiltration (p = 0.04), while HER2 overexpression was associated to better differentiated cases (p = 0.04) and to the absence of vascular infiltration (p = 0.02). MET expression, however, showed no association with the analyzed clinicopathological factors. This study highlights the role of tissue differentiation on pathological response to neoadjuvant chemotherapy in gastric cancer and shows no impact between FOXP3, HER2 and MET expression in terms of TRG.
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Díaz-Serrano A, Angulo B, Dominguez C, Pazo-Cid R, Salud A, Jiménez-Fonseca P, Leon A, Galan MC, Alsina M, Rivera F, Plaza JC, Paz-Ares L, Lopez-Rios F, Gómez-Martín C. Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive Advanced Gastric Cancer Treated with Trastuzumab. Oncologist 2018; 23:1092-1102. [PMID: 29700210 DOI: 10.1634/theoncologist.2017-0379] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 02/22/2018] [Indexed: 01/29/2023] Open
Abstract
BACKGROUND HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2-positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab-based chemotherapy in terms of OS and PFS. CONCLUSION Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2-positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC.
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Affiliation(s)
| | - Barbara Angulo
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Carolina Dominguez
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Roberto Pazo-Cid
- Medical Oncology Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Antonieta Salud
- Medical Oncology Unit, Hospital Universitario Arnau de Vilanova, Lérida, Spain
| | - Paula Jiménez-Fonseca
- Medical Oncology Department, Hospital Universitario Central de Asturias, Oviedo, Spain
| | - Ana Leon
- Medical Oncology Unit, Fundación Jimenez Diaz, Madrid, Spain
| | - Maria Carmen Galan
- Medical Oncology Department, Institut Català d'Oncologia, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Maria Alsina
- Medical Oncology Department, Hospital Universitari Vall d'Hebrón, Barcelona, Spain
| | - Fernando Rivera
- Medical Oncology Deparment, Hospital Universitario Marques de Valdecilla, Santander, Spain
| | - J Carlos Plaza
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Luis Paz-Ares
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Fernando Lopez-Rios
- Laboratorio Dianas Terapeuticas. Centro Integral Oncologico Clara Campal, Hospital Universitario HM Sanchinarro, Madrid, Spain
| | - Carlos Gómez-Martín
- Medical Oncology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
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Keller S, Zwingenberger G, Ebert K, Hasenauer J, Wasmuth J, Maier D, Haffner I, Schierle K, Weirich G, Luber B. Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines. Mol Oncol 2018; 12:441-462. [PMID: 29325228 PMCID: PMC5891041 DOI: 10.1002/1878-0261.12170] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 12/21/2017] [Accepted: 01/02/2018] [Indexed: 12/19/2022] Open
Abstract
The molecular mechanism of action of the HER2‐targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream‐acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI‐N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET‐amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
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Affiliation(s)
- Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Karolin Ebert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Jan Hasenauer
- Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Institute of Computational Biology, Neuherberg, Germany.,Department of Mathematical Modeling of Biological Systems, Center for Mathematics, Technische Universität München, Garching, Germany
| | - Jacqueline Wasmuth
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | | | | | - Katrin Schierle
- Institute of Pathology, Universitätsklinikum Leipzig, Germany
| | - Gregor Weirich
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Germany
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Szász AM, Lánczky A, Nagy Á, Förster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabó A, Győrffy B. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget 2018; 7:49322-49333. [PMID: 27384994 PMCID: PMC5226511 DOI: 10.18632/oncotarget.10337] [Citation(s) in RCA: 756] [Impact Index Per Article: 108.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2016] [Accepted: 06/13/2016] [Indexed: 02/07/2023] Open
Abstract
Introduction Multiple gene expression based prognostic biomarkers have been repeatedly identified in gastric carcinoma. However, without confirmation in an independent validation study, their clinical utility is limited. Our goal was to establish a robust database enabling the swift validation of previous and future gastric cancer survival biomarker candidates. Results The entire database incorporates 1,065 gastric carcinoma samples, gene expression data. Out of 29 established markers, higher expression of BECN1 (HR = 0.68, p = 1.5E-05), CASP3 (HR = 0.5, p = 6E-14), COX2 (HR = 0.72, p = 0.0013), CTGF (HR = 0.72, p = 0.00051), CTNNB1 (HR = 0.47, p = 4.3E-15), MET (HR = 0.63, p = 1.3E-05), and SIRT1 (HR = 0.64, p = 2.2E-07) correlated to longer OS. Higher expression of BIRC5 (HR = 1.45, p = 1E-04), CNTN1 (HR = 1.44, p = 3.5E- 05), EGFR (HR = 1.86, p = 8.5E-11), ERCC1 (HR = 1.36, p = 0.0012), HER2 (HR = 1.41, p = 0.00011), MMP2 (HR = 1.78, p = 2.6E-09), PFKB4 (HR = 1.56, p = 3.2E-07), SPHK1 (HR = 1.61, p = 3.1E-06), SP1 (HR = 1.45, p = 1.6E-05), TIMP1 (HR = 1.92, p = 2.2E- 10) and VEGF (HR = 1.53, p = 5.7E-06) were predictive for poor OS. MATERIALS AND METHODS We integrated samples of three major cancer research centers (Berlin, Bethesda and Melbourne datasets) and publicly available datasets with available follow-up data to form a single integrated database. Subsequently, we performed a literature search for prognostic markers in gastric carcinomas (PubMed, 2012–2015) and re-validated their findings predicting first progression (FP) and overall survival (OS) using uni- and multivariate Cox proportional hazards regression analysis. Conclusions The major advantage of our analysis is that we evaluated all genes in the same set of patients thereby making direct comparison of the markers feasible. The best performing genes include BIRC5, CASP3, CTNNB1, TIMP-1, MMP-2, SIRT, and VEGF.
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Affiliation(s)
- A Marcell Szász
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,2nd Department of Pathology, Semmelweis University, Budapest, Hungary
| | - András Lánczky
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
| | - Ádám Nagy
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary
| | - Susann Förster
- Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Kim Hark
- Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Jeffrey E Green
- Transgenic Oncogenesis and Genomics Section, Laboratory of Cancer Biology and Genetics, National Cancer Institute, Bethesda, Maryland, USA
| | - Alex Boussioutas
- Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
| | - Rita Busuttil
- Cancer Genetics and Genomics Laboratory, Peter MacCallum Cancer Centre, East Melbourne, Australia.,Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.,Department of Medicine, Royal Melbourne Hospital, The University of Melbourne, Melbourne, Australia
| | - András Szabó
- 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Balázs Győrffy
- MTA-TTK Lendület Cancer Biomarker Research Group, Budapest, Hungary.,2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary
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Zhang J, Guo L, Liu X, Li W, Ying J. MET overexpression, gene amplification and relevant clinicopathological features in gastric adenocarcinoma. Oncotarget 2018; 8:10264-10273. [PMID: 28052014 PMCID: PMC5354657 DOI: 10.18632/oncotarget.14382] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2016] [Accepted: 12/13/2016] [Indexed: 12/21/2022] Open
Abstract
This study was conducted to investigate the expression of MET in Chinese gastric adenocarcinoma cohort, the correlation between MET overexpression and clinical pathological features, HER2 expression and MET gene amplification. A total of 816 gastric adenocarcinoma patients were included and MET and HER2 immunohistochemical (IHC) staining were performed. IHC and dual-color silver in situ hybridization analysis were performed in the tissue microarrays, constructed from the 240 patients who were randomly selected. MET overexpression (IHC 3+) was observed in 6.0% (49/816) of the cohort. MET overexpression rate was higher in patients with poor prognostic factors, such as clinical stages III/IV (p =0.012) and pathologic stages T3/T4 (p =0.027). The HER2 overexpression (IHC 3+) rate was 8.8% (72/816) and MET overexpression rate was higher in HER2 positive patients (9.7%, 7/72). A high concordance rate (94.6%) between MET overexpression and gene amplification was demonstrated. Therefore, MET overexpression could serve as a prognostic biomarker and a potential therapeutic target for gastric cancer.
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Affiliation(s)
- Jing Zhang
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Lei Guo
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Xiuyun Liu
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenbin Li
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Jianming Ying
- Department of Pathology, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
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PKG II reverses HGF-triggered cellular activities by phosphorylating serine 985 of c-Met in gastric cancer cells. Oncotarget 2018; 7:34190-200. [PMID: 27147579 PMCID: PMC5085148 DOI: 10.18632/oncotarget.9074] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 04/10/2016] [Indexed: 12/15/2022] Open
Abstract
Previous studies showed that type II cGMP-dependent protein kinase G (PKG II) could inhibit the activation of epidermal growth factor receptor (EGFR). Both c-Met and EGFR belong to family of receptor tyrosine kinases (RTKs) and have high molecular analogy. However, the effect of PKG II on c-Met activation is unclear. This study was designed to investigate the inhibitory effect of PKG II on the activation of c-Met and consequent biological activities. The results from CCK8 assay, Transwell assay and TUNEL assay showed that HGF enhanced cell proliferation and migration, and decreased cell apoptosis. Activated PKG II reversed the above changes caused by HGF. Immunoprecipitation and Western blotting results showed that PKG II could bind with c-Met and phosphorylate its Ser985, and thereby inhibited HGF-induced activation of c-Met and MAPK/ERK and PI3K/Akt/mTOR mediated signal transduction. When Ser985 of c-Met was mutated to Alanine for preventing phosphorylation of this site, the blocking effect of PKG II on c-Met activation was annulled. When Ser985 of c-Met was mutated to Aspartic acid for mimicking phosphorylation of this site, HGF-induced activation of c-Met was prevented. In conclusion, the results indicated that PKG II could block c-Met activation via phosphorylating Ser985 of this RTK.
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Kumar R, Jain AG, Rashid MU, Ali S, Khetpal N, Hussain I, Ahmad S. HGFR and FGR2: Their Roles in Progression and Metastasis of Esophageal Cancer. ROLE OF TYROSINE KINASES IN GASTROINTESTINAL MALIGNANCIES 2018:1-14. [DOI: 10.1007/978-981-13-1486-5_1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Joung JY, Kwon WA, Lim J, Oh CM, Jung KW, Kim SH, Seo HK, Park WS, Chung J, Lee KH, Won YJ. Second Primary Cancer Risk among Kidney Cancer Patients in Korea: A Population-Based Cohort Study. Cancer Res Treat 2018; 50:293-301. [PMID: 28421722 PMCID: PMC5784635 DOI: 10.4143/crt.2016.543] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2016] [Accepted: 04/14/2017] [Indexed: 12/23/2022] Open
Abstract
PURPOSE Secondary primary cancers (SPCs) commonly arise in patients with renal cell carcinoma (RCC). We designed the present study to estimate the SPC incidence in Korean patients with RCC. MATERIALS AND METHODS The study cohort was population-based and consisted of 40,347 individuals from the Korean Central Cancer Registry who were diagnosed with primary renal cancer between 1993 and 2013. Standardized incidence ratios (SIRs) for SPCs were estimated for different ages at diagnosis, latencies, diagnostic periods, and treatments. RESULTS For patients with primary RCC, the risk of developing a SPC was higher than the risk of developing cancer in the general population (SIR, 1.13; 95% confidence interval, 1.08 to 1.18). Most cancer types showed higher incidences in patients with RCC than in the general population. However, the relative incidence of gastric cancer as an SPC varied by age. Gastric cancer incidence was elevated in young patients (< 30 years) with RCC, but reduced in older (≥ 30) patients with RCC. Patients with advanced RCC died prematurely, regardless of SPC development. In contrast, those with early-stage RCC survived for longer periods, although SPC development affected their post-RCC survival. After SPC development, women had better survival than men. CONCLUSION In Korean patients with primary RCC, the incidence of SPC was 13% higher than the incidence of cancer in the general population. These findings may play important roles in the conduct of follow-up evaluations and education for patients with RCC.
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Affiliation(s)
- Jae Young Joung
- Center for Prostate Cancer, National Cancer Center, Goyang, Korea
| | - Whi-An Kwon
- Department of Urology, Institute of Wonkwang Medical Science, Wonkwang University Sanbon Hospital, Wonkwang University School of Medicine, Gunpo, Korea
| | - Jiwon Lim
- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, Korea
| | - Chang-Mo Oh
- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, Korea
| | - Kyu-Won Jung
- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, Korea
| | - Sung Han Kim
- Center for Prostate Cancer, National Cancer Center, Goyang, Korea
| | - Ho Kyung Seo
- Center for Prostate Cancer, National Cancer Center, Goyang, Korea
| | - Weon Seo Park
- Center for Prostate Cancer, National Cancer Center, Goyang, Korea
| | - Jinsoo Chung
- Center for Prostate Cancer, National Cancer Center, Goyang, Korea
| | - Kang Hyun Lee
- Center for Prostate Cancer, National Cancer Center, Goyang, Korea
| | - Young-Joo Won
- Cancer Registration and Statistics Branch, National Cancer Center, Goyang, Korea
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The Prognostic Significance of c-MET and EGFR Overexpression in Resected Gastric Adenocarcinomas. Am J Clin Oncol 2017; 40:543-551. [PMID: 26125303 DOI: 10.1097/coc.0000000000000202] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Epidermal growth factor receptor (EGFR) and c-MET are tyrosine kinase growth factor receptors implicated in gastric cancer (GC), and their pathways appear to be interdependent. The aim of this study was to investigate the prognostic value of EGFR and c-MET protein overexpression by immunohistochemistry in Canadian patients with resected GC and correlate it with clinicopathologic characteristics and overall survival (OS). MATERIALS AND METHODS Tissue microarray blocks were constructed from 120 resected GCs stained with EGFR and c-MET and scored semiquantitatively (0 to 3+). Each receptor's expression was compared with clinicopathologic characteristics and survival. Descriptive statistics, Kaplan-Meyer, and Cox regression were used for statistical analyses. RESULTS Of the 113 interpretable cases, overexpression of EGFR and c-MET was noted in 17 (15%) and 65 (57%), respectively; coexpression of EGFR and c-MET was observed in 12 (10%) of GC. EGFR and c-MET overexpression correlated with poor OS: median 13 versus 30 months in EGFR positive versus negative GC (hazard ratio [HR]=1.67, P=0.11); 27 versus 49 months in c-MET positive versus negative GC (HR=1.17, P=0.49), respectively. GC coexpressing EGFR and c-MET was significantly correlated with poor survival: 12 versus 29 months in double-positive versus rest of tumors both in univariate (HR=2.62, P=0.003) and multivariate analyses (HR=2.58, P=0.01). CONCLUSIONS This study describes the prevalence and prognostic value of EGFR and c-MET in a Canadian population of patients undergoing curative intent resection for GC. Both c-MET and EGFR overexpression trended toward poor OS, but only the group with EGFR+/c-MET+ GC reached statistical significance on multivariate analysis.
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Jørgensen JT, Nielsen KB, Mollerup J, Jepsen A, Go N. Detection of MET amplification in gastroesophageal tumor specimens using IQFISH. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:458. [PMID: 29285491 PMCID: PMC5733332 DOI: 10.21037/atm.2017.09.07] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2017] [Accepted: 09/01/2017] [Indexed: 12/17/2022]
Abstract
BACKGROUND The gene mesenchymal epithelial transition factor (MET) is a proto-oncogene that encodes a transmembrane receptor with intrinsic tyrosine kinase activity known as Met or cMet. MET is found to be amplified in several human cancers including gastroesophageal cancer. METHODS Here we report the MET amplification prevalence data from 159 consecutive tumor specimens from patients with gastric (G), gastroesophageal junction (GEJ) and esophageal (E) adenocarcinoma, using a novel fluorescence in situ hybridization (FISH) assay, MET/CEN-7 IQFISH Probe Mix [an investigational use only (IUO) assay]. MET amplification was defined as a MET/CEN-7 ratio ≥2.0. Furthermore, the link between the MET signal distribution and amplification status was investigated. RESULTS The prevalence of MET amplification was found to be 6.9%. The FISH assay demonstrated a high inter-observer reproducibility. The inter-observer results showed a 100% overall agreement with respect to the MET status (amplified/non-amplified). The inter-observer CV was estimated to 11.8% (95% CI: 10.2-13.4). For the signal distribution, the inter-observer agreement was reported to be 98.7%. We also report an association of MET amplification and a unique signal distribution pattern in the G/GEJ/E tumor specimens. We found that the prevalence of MET amplification was markedly higher in tumors specimens with a heterogeneous (66.7%) versus homogeneous (2.0%) signal distribution. Furthermore, specimens with a heterogeneous signal distribution had a statically significantly higher median MET/CEN-7 ratio (2.35 versus 1.04; P<0.0001). CONCLUSIONS The novel FISH assay showed a high inter-observer reproducibility both with respect to amplification status and signal distribution. Based on the finding in the study it is suggested that MET amplification mainly is associated with tumor cells that is represented by a heterogonous growth pattern.
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Affiliation(s)
- Jan Trøst Jørgensen
- Department of Companion Diagnostic Research, Dx-Rx Institute, Fredensborg, Denmark
| | - Karsten Bork Nielsen
- R&D, Diagnostics and Genomics Group, Agilent Technologies Denmark Aps, Glostrup, Denmark
| | - Jens Mollerup
- R&D, Diagnostics and Genomics Group, Agilent Technologies Denmark Aps, Glostrup, Denmark
| | - Anna Jepsen
- R&D, Diagnostics and Genomics Group, Agilent Technologies Denmark Aps, Glostrup, Denmark
| | - Ning Go
- Medical Sciences, Amgen Inc., Thousand Oaks, CA, USA
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50
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Kwon MJ, Kim RN, Song K, Jeon S, Jeong HM, Kim JS, Han J, Hong S, Oh E, Choi JS, An J, Pollack JR, Choi YL, Park CK, Shin YK. Genes co-amplified with ERBB2 or MET as novel potential cancer-promoting genes in gastric cancer. Oncotarget 2017; 8:92209-92226. [PMID: 29190909 PMCID: PMC5696175 DOI: 10.18632/oncotarget.21150] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Accepted: 08/27/2017] [Indexed: 12/18/2022] Open
Abstract
Gastric cancer (GC), one of the most common cancers worldwide, has a high mortality rate due to limited treatment options. Identifying novel and promising molecular targets is a major challenge that must be overcome if treatment of advanced GC is to be successful. Here, we used comparative genomic hybridization and gene expression microarrays to examine genome-wide DNA copy number alterations (CNAs) and global gene expression in 38 GC samples from old and young patients. We identified frequent CNAs, which included copy number gains on chromosomes 3q, 7p, 8q, 20p, and 20q and copy number losses on chromosomes 19p and 21p. The most frequently gained region was 7p21.1 (55%), whereas the most frequently deleted region was 21p11.1 (50%). Recurrent highly amplified regions 17q12 and 7q31.1-7q31.31 harbored two well-known oncogenes: ERBB2 and MET. Correlation analysis of CNAs and gene expression levels identified CAPZA2 (co-amplified with MET) and genes GRB7, MIEN1, PGAP3, and STARD3 (co-amplified with ERBB2) as potential candidate cancer-promoting genes (CPGs). Public dataset analysis confirmed co-amplification of these genes with MET or ERBB2 in GC tissue samples, and revealed that high expression (except for PGAP3) was significantly associated with shorter overall survival. Knockdown of these genes using small interfering RNA led to significant suppression of GC cell proliferation and migration. Reduced GC cell proliferation mediated by CAPZA2 knockdown was attributable to attenuated cell cycle progression and increased apoptosis. This study identified novel candidate CPGs co-amplified with MET or ERBB2, and suggests that they play a functional role in GC.
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Affiliation(s)
- Mi Jeong Kwon
- College of Pharmacy, Kyungpook National University, Daegu, Korea.,Research Institute of Pharmaceutical Sciences, College of Pharmacy, Kyungpook National University, Daegu, Korea
| | - Ryong Nam Kim
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea
| | - Kyoung Song
- R&D center, ABION Inc., Guro-gu, Seoul, Korea
| | - Sinyoung Jeon
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Hae Min Jeong
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Joo Seok Kim
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Jinil Han
- Gencurix, Inc., Guro-gu, Seoul, Korea
| | - Sungyoul Hong
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea
| | - Ensel Oh
- Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jong-Sun Choi
- The Center for Anti-cancer Companion Diagnostics, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea
| | - Jungsuk An
- Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea
| | - Jonathan R Pollack
- Department of Pathology, Stanford University School of Medicine, Stanford, California, United States of America
| | - Yoon-La Choi
- Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea
| | - Cheol-Keun Park
- Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Young Kee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy, Seoul National University, Seoul, Korea.,Tumor Microenvironment Global Core Research Center, Seoul National University, Seoul, Korea.,The Center for Anti-cancer Companion Diagnostics, Institutes of Entrepreneurial BioConvergence, Seoul National University, Seoul, Korea.,Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Korea
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