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Lin H, Qu L, Wei H, Guo M, Chen X, Lin Q, Zhang H, Dai S, Chen Y. Characterization of Bozitinib as a potential therapeutic agent for MET-amplified gastric cancer. Commun Biol 2025; 8:134. [PMID: 39875456 PMCID: PMC11775172 DOI: 10.1038/s42003-025-07490-5] [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: 08/08/2024] [Accepted: 01/08/2025] [Indexed: 01/30/2025] Open
Abstract
Hyperactive c-Met signaling pathway caused by altered MET is a common mechanism underlying gastric cancer and represents an attractive target for the treatment of gastric cancer with MET alterations. However, no c-Met kinase inhibitors are currently approved specifically for the treatment of c-Met-amplified gastric cancer. Recently, bozitinib, a highly selective c-Met kinase inhibitor, has shown remarkable potency in selectively inhibiting MET-altered non-small cell lung cancer and secondary glioblastoma. In this study, we investigate the antitumor activity of bozitinib against MET-amplified gastric cancer and elucidate its molecular mechanism. Bozitinib demonstrates a strong effect on MET-amplified gastric cancer cells by blocking the c-Met signaling pathway, leading to the inhibition of cell proliferation and survival, as well as the induction of G0/G1 phase arrest and apoptosis. Structurally, bozitinib is optimally embedded in the ATP pocket of c-Met and firmly binds via an extensive interaction network. In addition, bozitinib efficiently inhibits c-Met resistance-conferring mutations G1163R and Y1230H, although its potency is significantly decreased against the D1228N and Y1230C mutations. Overall, our study reveals the molecular mechanism of bozitinib against c-Met, highlights its ability to overcome acquired resistance mutations, and provides valuable insights into further design and improvement of selective c-Met inhibitors.
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Affiliation(s)
- Hang Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Lingzhi Qu
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Hudie Wei
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ming Guo
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Xiaojuan Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Qianmeng Lin
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Huajun Zhang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
- Department of Ultrasound Imaging, Xiangya Hospital, Central South University, Changsha, China
| | - Shuyan Dai
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics & State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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Elasbali AM, Anjum F, Al-Ghabban BA, Shafie A, Mohammad T, Hassan MI. Phytochemicals Neogitogenin and Samogenin Hold Potentials for Hepatocyte Growth Factor Receptor-Targeted Cancer Treatment. OMICS : A JOURNAL OF INTEGRATIVE BIOLOGY 2024; 28:573-583. [PMID: 39388097 DOI: 10.1089/omi.2024.0169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2024]
Abstract
Protein kinases are key targets for cancer therapies, with the c-Met receptor tyrosine kinase (MET) and its ligand, hepatocyte growth factor, playing a role in various cancers, including non-small cell lung cancer, gastric cancer, and hepatocellular carcinoma. Although small-molecule inhibitors have been designed to target MET, the development of drug resistance remains a significant challenge to advancing therapeutic strategies. In this study, we employed virtual screening of plant-based compounds sourced from the IMPPAT 2.0 databank to identify potent inhibitors of MET. Preliminary filtering based on the physicochemical parameters following Lipinski's rule of five and pan-assay interference compounds criteria were applied to prioritize hits. Subsequent molecular docking, pharmacokinetic evaluation, prediction of activity spectra for biologically active substances, and specificity assessments facilitated the identification of two promising phytochemicals, neogitogenin and samogenin. Both phytochemicals exhibited considerable drug-like properties with notable binding affinity and selectivity toward MET. Molecular dynamics simulation studies showed the conformational stability of MET with neogitogenin and samogenin. Taken together, these findings suggest that neogitogenin and samogenin hold potential as lead molecules for the development of MET-targeted therapeutics. We call for further evaluations of these phytochemicals in preclinical and experimental studies for anticancer drug discovery and development.
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Affiliation(s)
- Abdelbaset Mohamed Elasbali
- Department of Clinical Laboratory Science, College of Applied Medical Sciences-Qurayyat, Jouf University, Qurayyat, KSA, Saudi Arabia
| | - Farah Anjum
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | - Alaa Shafie
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, New Delhi, India
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Khaleel AQ, Alshahrani MY, Rizaev JA, Malathi H, Devi S, Pramanik A, Mustafa YF, Hjazi A, Muazzamxon I, Husseen B. siRNA-based strategies to combat drug resistance in gastric cancer. Med Oncol 2024; 41:293. [PMID: 39428440 DOI: 10.1007/s12032-024-02528-w] [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: 08/17/2024] [Accepted: 09/27/2024] [Indexed: 10/22/2024]
Abstract
Chemotherapy is a key treatment option for gastric cancer, but over 50% of patients develop either inherent or acquired resistance to these drugs, resulting in a 5-year survival rate of only about 20%. The primary treatment for advanced gastric cancer typically involves chemotherapy based on platinum or fluorouracil. Several factors can contribute to platinum resistance, including decreased drug uptake, increased drug efflux or metabolism, enhanced DNA repair, activation of pro-survival pathways, and inhibition of pro-apoptotic pathways. In recent years, there has been significant progress in biology aimed at finding innovative and more effective methods to overcome chemotherapy resistance. Small interfering RNAs (siRNAs) have emerged as a significant advancement in gene expression regulation, showing promise in enhancing the sensitivity of gastric cancer cells to chemotherapy drugs. However, siRNA therapies still face major challenges, particularly in terms of stability and efficient delivery in vivo. This article discusses the advances in siRNA therapy and its potential role in overcoming resistance to chemotherapeutic drugs such as cisplatin, 5-FU, doxorubicin, and paclitaxel in the treatment of gastric cancer.
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Affiliation(s)
- Abdulrahman Qais Khaleel
- Department of Medical Instruments Engineering, College of Engineering, University of Al Maarif, Ramadi, Al Anbar, 31001, Iraq.
| | - Mohammad Y Alshahrani
- Department of Clinical Laboratory Sciences, College of Applied Medical Science, King Khalid University, Abha, Saudi Arabia
| | - Jasur Alimdjanovich Rizaev
- Department of Public Health and Healthcare Management, Rector, Samarkand State Medical University, 18 Amir Temur Street, Samarkand, Uzbekistan.
| | - H Malathi
- Department of Biotechnology and Genetics, School of Sciences Jain (Deemed to be University), Bangalore, Karnataka, India
| | - Seema Devi
- Chandigarh Pharmacy College, Chandigarh Group of Colleges, Jhanjheri, Mohali, 140307, Punjab, India
| | - Atreyi Pramanik
- School of Applied and Life Sciences, Division of Research and Innovation, Uttaranchal University, Dehradun, Uttarakhand, India
| | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Ahmed Hjazi
- Department of Medical Laboratory, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, 11942, Al-Kharj, Saudi Arabia
| | - Ismoilova Muazzamxon
- Department of Propaedeutics of Internal Diseases, Fergana Medical Institute of Public Health, Fergana, Uzbekistan
- Western Caspian University, Scientific Researcher, Baku, Azerbaijan
| | - Beneen Husseen
- Medical Laboratory Technique College, the Islamic University, Najaf, Iraq
- Medical Laboratory Technique College, the Islamic University of Al Diwaniyah, Al Diwaniyah, Iraq
- Medical Laboratory Technique College, the Islamic University of Babylon, Babylon, Iraq
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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: 5] [Impact Index Per Article: 5.0] [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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Zeng Z, Zhu Q. Progress and prospects of biomarker-based targeted therapy and immune checkpoint inhibitors in advanced gastric cancer. Front Oncol 2024; 14:1382183. [PMID: 38947886 PMCID: PMC11211377 DOI: 10.3389/fonc.2024.1382183] [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: 02/05/2024] [Accepted: 05/24/2024] [Indexed: 07/02/2024] Open
Abstract
Gastric cancer and gastroesophageal junction cancer represent the leading cause of tumor-related death worldwide. Although advances in immunotherapy and molecular targeted therapy have expanded treatment options, they have not significantly altered the prognosis for patients with unresectable or metastatic gastric cancer. A minority of patients, particularly those with PD-L1-positive, HER-2-positive, or MSI-high tumors, may benefit more from immune checkpoint inhibitors and/or HER-2-directed therapies in advanced stages. However, for those lacking specific targets and unique molecular features, conventional chemotherapy remains the only recommended effective and durable regimen. In this review, we summarize the roles of various signaling pathways and further investigate the available targets. Then, the current results of phase II/III clinical trials in advanced gastric cancer, along with the superiorities and limitations of the existing biomarkers, are specifically discussed. Finally, we will offer our insights in precision treatment pattern when encountering the substantial challenges.
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Affiliation(s)
| | - Qing Zhu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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Jin F, Lin Y, Yuan W, Wu S, Yang M, Ding S, Liu J, Chen Y. Recent advances in c-Met-based dual inhibitors in the treatment of cancers. Eur J Med Chem 2024; 272:116477. [PMID: 38733884 DOI: 10.1016/j.ejmech.2024.116477] [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: 03/25/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024]
Abstract
The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.
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Affiliation(s)
- Fanqi Jin
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Yihan Lin
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Weidong Yuan
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Shuang Wu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Min Yang
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Shi Ding
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China
| | - Ju Liu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China.
| | - Ye Chen
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China.
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8
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Li SC, Gu LH, Wang YF, Wang LM, Chen L, Giesy JP, Tuo X, Xu WL, Wu QH, Liu YQ, Wu MH, Diao YY, Zeng HH, Zhang QB. A proteomic study on gastric impairment in rats caused by microcystin-LR. THE SCIENCE OF THE TOTAL ENVIRONMENT 2024; 917:169306. [PMID: 38103614 DOI: 10.1016/j.scitotenv.2023.169306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 11/28/2023] [Accepted: 12/10/2023] [Indexed: 12/19/2023]
Abstract
Microcystins (MCs) are the most common cyanobacterial toxins. Epidemiological investigation showed that exposure to MCs can cause gastro-intestinal symptoms, gastroenteritis and gastric cancer. MCs can also accumulate in and cause histopathological damage to stomach. However, the exact mechanisms by which MCs cause gastric injury were unclear. In this study, Wistar rats were administrated 50, 75 or 100 μg microcystin-LR (MC-LR)/kg, body mass (bm) via tail vein, and histopathology, response of anti-oxidant system and the proteome of gastric tissues at 24 h after exposure were studied. Bleeding of fore-stomach and gastric corpus, inflammation and necrosis in gastric corpus and exfoliation of mucosal epithelial cells in gastric antrum were observed following acute MC-LR exposure. Compared with controls, activities of superoxide dismutase (SOD) were significantly greater in gastric tissues of exposed rats, while activities of catalase (CAT) were less in rats administrated 50 μg MC-LR/kg, bm, and concentrations of glutathione (GSH) and malondialdehyde (MDA) were greater in rats administrated 75 or 100 μg MC-LR/kg, bm. These results indicated that MC-LR could disrupt the anti-oxidant system and cause oxidative stress. The proteomic results revealed that MC-LR could affect expressions of proteins related to cytoskeleton, immune system, gastric functions, and some signaling pathways, including platelet activation, complement and coagulation cascades, and ferroptosis. Quantitative real-time PCR (qRT-PCR) analysis showed that transcriptions of genes for ferroptosis and gastric function were altered, which confirmed results of proteomics. Overall, this study illustrated that MC-LR could induce gastric dysfunction, and ferroptosis might be involved in MC-LR-induced gastric injury. This study provided novel insights into mechanisms of digestive diseases induced by MCs.
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Affiliation(s)
- Shang-Chun Li
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Li-Hong Gu
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Yan-Fang Wang
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Li-Mei Wang
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Liang Chen
- Qilu Lake Field Scientific Observation and Research Station for Plateau Shallow Lake in Yunnan Province, Institute for Ecological Research and Pollution Control of Plateau Lakes, School of Ecology and Environmental Science, Yunnan University, Kunming 650500, China; Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; State Key Laboratory of Eco-hydraulics in Northwest Arid Region, Faculty of Water Resources and Hydroelectric Engineering, Xi'an University of Technology, Xi'an 710048, China.
| | - John P Giesy
- Department of Veterinary Biomedical Sciences, Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5B3, Canada
| | - Xun Tuo
- College of Chemistry, Nanchang University, Nanchang 330031, China
| | - Wen-Li Xu
- Donghu Experimental Station of Lake Ecosystems, State Key Laboratory of Freshwater Ecology and Biotechnology, Institute of Hydrobiology, Chinese Academy of Sciences, Wuhan 430072, China; University of Chinese Academy of Sciences, Beijing 100049, China
| | - Qian-Hui Wu
- School of Ecology and Environment, Anhui Normal University, Wuhu 241002, China
| | - Yi-Qing Liu
- Qilu Lake Field Scientific Observation and Research Station for Plateau Shallow Lake in Yunnan Province, Institute for Ecological Research and Pollution Control of Plateau Lakes, School of Ecology and Environmental Science, Yunnan University, Kunming 650500, China
| | - Ming-Huo Wu
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Yang-Yang Diao
- Department of Pediatrics, Southwest Medical University, Luzhou 646000, China
| | - Hao-Hang Zeng
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China
| | - Qing-Bi Zhang
- Environmental Health Effects and Risk Assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou 646000, China.
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Xiao H, Huang J, Wu H, Li Y, Wang Y. Pro-tumorigenic activity of PYCR1 in gastric cancer through regulating the PI3K/AKT signaling. Heliyon 2024; 10:e26883. [PMID: 38455525 PMCID: PMC10918153 DOI: 10.1016/j.heliyon.2024.e26883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2023] [Revised: 02/08/2024] [Accepted: 02/21/2024] [Indexed: 03/09/2024] Open
Abstract
Background The primary objective of this investigation was to assess the impact of pyrroline-5-carboxylate reductase 1 (PYCR1) on the progression of gastric cancer (GC), specifically focusing on tumor growth and metastatic potential. Methods Surgical specimens from patients with different stages of GC were assayed for PYCR1 expression using immunohistochemistry. PYCR1 expression was manipulated by depletion or overexpression approaches in GC cells, and these cells were applied to explore the functional roles of PYCR1. Expression of apoptosis- and metastasis-related markers was quantified through quantitative real-time PCR and Western blot. Results Higher PYCR1 expression was ascertained in surgical specimens from patients with GC as compared to noncancerous adjacent tissues. Additionally, PYCR1 overexpression in GC tissues was linked to adverse clinical outcomes. The depletion of PYCR1 in GC cells resulted in a pronounced reduction in proliferation, the induction of apoptosis, and the attenuation of invasion and metastasis. Conversely, its ectopic expression notably augmented proliferation, restricted apoptosis, and stimulated invasion and metastasis. In addition, the knockdown of PYCR1 resulted in a significant elevation in the activation of caspase 3, a key protein involved in apoptosis. This depletion also led to a decrease in the activation or expression of proteins associated with metastasis, such as phosphorylated (p)-phosphatidylinositol 3-kinase (PI3K), p-AKT serine/threonine kinase (AKT), and snail family transcriptional repressor 1 (Snail). Additionally, it resulted in an upregulation of E-cadherin expression. Conversely, the overexpression of PYCR1 notably increased the levels of p-PI3K, p-AKT, and Snail, while simultaneously reducing E-cadherin expression. Conclusion PYCR1, by activating PI3K/AKT signaling, assumes a crucial role in governing malignant characteristics of GC cells, including proliferation, apoptosis, and metastasis. These findings underscore the promising potential of PYCR1 as a diagnostic biomarker and a target for tailored therapeutic interventions in patients with GC.
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Affiliation(s)
- Huijie Xiao
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Jiannan Huang
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, China
| | - Haitao Wu
- Cancer Center, First Hospital of Jilin University, Changchun 130021, China
| | - YuYing Li
- Cancer Center, First Hospital of Jilin University, Changchun 130021, China
| | - Yizhuo Wang
- Cancer Center, First Hospital of Jilin University, Changchun 130021, China
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10
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Wang J, Yao G, Zhang B, Zhao Z, Fan Y. Interaction between miR‑206 and lncRNA MALAT1 in regulating viability and invasion in hepatocellular carcinoma. Oncol Lett 2024; 27:5. [PMID: 38028177 PMCID: PMC10665983 DOI: 10.3892/ol.2023.14138] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2022] [Accepted: 06/19/2023] [Indexed: 12/01/2023] Open
Abstract
MicroRNAs (miRNAs) are strongly associated to the progression of hepatocellular carcinoma (HCC), which presents a high potential for diagnosis and treatment; however, the role of miRNAs is still largely unknown. The aim of the present study was to examine the expression and the biological role of miRNA (miR)-206 in the development of HCC, and to identify the underlying molecular mechanism. Results from this study show that miR-206 was significantly downregulated in HCC tissues and cell lines. It was observed that low expression of miR-206 was linked to advanced TNM stage, tumor nodularity and venous infiltration in patients with HCC; low miR-206 expression was associated with shorter survival times. miR-206 overexpression using miR-206 mimics notably decreased the proliferative ability and increased apoptosis of MHCC97-H and HCCLM3 HCC cell lines. Overexpression of miR-206 suppressed invasiveness associated with reduced epithelial-mesenchymal transition. Moreover, the c-Met oncogene, which is upregulated in HCC tissues, was negatively associated with the expression of miR-206. Notably, it was shown that miR-206 may exert its antitumor effect through suppressing c-Met/Akt/mTOR signaling. Low expression of miR-206 was shown to be regulated by lncRNA MALAT1 in HCC. Collectively, this study presented evidence that miR-206 was controlled by lncRNA MALAT1 and partially suppressed the proliferation and invasion of HCC through the c-Met/Akt/mTOR signaling pathway. According to these results, understanding MALAT1/miR-206-dependent regulation may lead to potential approaches for diagnosis and prospective treatment of HCC.
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Affiliation(s)
- Jun Wang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Guoliang Yao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Beike Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Zerui Zhao
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
| | - Yonggang Fan
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471003, P.R. China
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11
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Baccili Cury Megid T, Farooq AR, Wang X, Elimova E. Gastric Cancer: Molecular Mechanisms, Novel Targets, and Immunotherapies: From Bench to Clinical Therapeutics. Cancers (Basel) 2023; 15:5075. [PMID: 37894443 PMCID: PMC10605200 DOI: 10.3390/cancers15205075] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 10/16/2023] [Accepted: 10/17/2023] [Indexed: 10/29/2023] Open
Abstract
Gastric cancer is a global health concern, ranking fifth in cancer diagnoses and fourth in cancer-related deaths worldwide. Despite recent advancements in diagnosis, most cases are detected at advanced stages, resulting in poor outcomes. However, recent breakthroughs in genome analysis have identified biomarkers that hold positive clinical significance for GC treatment. These biomarkers and classifications offer the potential for more precise diagnostic and therapeutic approaches for GC patients. In this review, we explore the classification and molecular pathways in this disease, highlighting potential biomarkers that have emerged in recent studies including targeted therapies and immunotherapies. These advancements provide a promising direction for improving the management of GC.
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Affiliation(s)
| | | | | | - Elena Elimova
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; (T.B.C.M.); (A.R.F.); (X.W.)
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12
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Wang C, Lu X. Targeting MET: Discovery of Small Molecule Inhibitors as Non-Small Cell Lung Cancer Therapy. J Med Chem 2023. [PMID: 37262349 DOI: 10.1021/acs.jmedchem.3c00028] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.
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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
| | - Xiaoyun Lu
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450001, China
- 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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13
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Pawluczuk E, Łukaszewicz-Zając M, Mroczko B. The Comprehensive Analysis of Specific Proteins as Novel Biomarkers Involved in the Diagnosis and Progression of Gastric Cancer. Int J Mol Sci 2023; 24:ijms24108833. [PMID: 37240178 DOI: 10.3390/ijms24108833] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2023] [Revised: 05/12/2023] [Accepted: 05/14/2023] [Indexed: 05/28/2023] Open
Abstract
Gastric cancer (GC) cases are predicted to rise by 2040 to approximately 1.8 million cases, while GC-caused deaths to 1.3 million yearly worldwide. To change this prognosis, there is a need to improve the diagnosis of GC patients because this deadly malignancy is usually detected at an advanced stage. Therefore, new biomarkers of early GC are sorely needed. In the present paper, we summarized and referred to a number of original pieces of research concerning the clinical significance of specific proteins as potential biomarkers for GC in comparison to well-established tumor markers for this malignancy. It has been proved that selected chemokines and their specific receptors, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR), specific proteins such as interleukin 6 (IL-6) and C-reactive protein (CRP), matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS), as well as DNA- and RNA-based biomarkers, and c-MET (tyrosine-protein kinase Met) play a role in the pathogenesis of GC. Based on the recent scientific literature, our review indicates that presented specific proteins are potential biomarkers in the diagnosis and progression of GC as well as might be used as prognostic factors of GC patients' survival.
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Affiliation(s)
- Elżbieta Pawluczuk
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
| | - Marta Łukaszewicz-Zając
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15a, 15-269 Bialystok, Poland
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland
- Department of Biochemical Diagnostics, Medical University of Bialystok, Waszyngtona 15a, 15-269 Bialystok, Poland
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14
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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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15
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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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16
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Lei ZN, Teng QX, Tian Q, Chen W, Xie Y, Wu K, Zeng Q, Zeng L, Pan Y, Chen ZS, He Y. Signaling pathways and therapeutic interventions in gastric cancer. Signal Transduct Target Ther 2022; 7:358. [PMID: 36209270 PMCID: PMC9547882 DOI: 10.1038/s41392-022-01190-w] [Citation(s) in RCA: 121] [Impact Index Per Article: 40.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2022] [Revised: 08/14/2022] [Accepted: 09/07/2022] [Indexed: 11/23/2022] Open
Abstract
Gastric cancer (GC) ranks fifth in global cancer diagnosis and fourth in cancer-related death. Despite tremendous progress in diagnosis and therapeutic strategies and significant improvements in patient survival, the low malignancy stage is relatively asymptomatic and many GC cases are diagnosed at advanced stages, which leads to unsatisfactory prognosis and high recurrence rates. With the recent advances in genome analysis, biomarkers have been identified that have clinical importance for GC diagnosis, treatment, and prognosis. Modern molecular classifications have uncovered the vital roles that signaling pathways, including EGFR/HER2, p53, PI3K, immune checkpoint pathways, and cell adhesion signaling molecules, play in GC tumorigenesis, progression, metastasis, and therapeutic responsiveness. These biomarkers and molecular classifications open the way for more precise diagnoses and treatments for GC patients. Nevertheless, the relative significance, temporal activation, interaction with GC risk factors, and crosstalk between these signaling pathways in GC are not well understood. Here, we review the regulatory roles of signaling pathways in GC potential biomarkers, and therapeutic targets with an emphasis on recent discoveries. Current therapies, including signaling-based and immunotherapies exploited in the past decade, and the development of treatment for GC, particularly the challenges in developing precision medications, are discussed. These advances provide a direction for the integration of clinical, molecular, and genomic profiles to improve GC diagnosis and treatments.
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Affiliation(s)
- Zi-Ning Lei
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qiu-Xu Teng
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA
| | - Qin Tian
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Wei Chen
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Yuhao Xie
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA
| | - Kaiming Wu
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Qianlin Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China
| | - Leli Zeng
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Yihang Pan
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
| | - Zhe-Sheng Chen
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
- Institute for Biotechnology, St. John's University, Queens, NY, 11439, USA.
| | - Yulong He
- Guangdong Provincial Key Laboratory of Digestive Cancer Research, Digestive Diseases Center, Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-Sen University, 518107, Shenzhen, Guangdong, China.
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17
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Zhang Z, Miao L, Wang S, Zhao Y, Xie Y, Yun H, Ren Z, Wang G, Teng M, Li Y. Study on the expression of c-Met in gastric cancer and its correlation with preoperative serum tumor markers and prognosis. World J Surg Oncol 2022; 20:204. [PMID: 35710379 PMCID: PMC9202172 DOI: 10.1186/s12957-022-02659-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 05/28/2022] [Indexed: 12/04/2022] Open
Abstract
Background Studies have found that c-Met plays a critical role in the progression of solid tumors. This study aimed to investigate the expression of c-Met in gastric cancer (GC) and its correlation with preoperative serum tumor markers and prognosis, in order to provide a more theoretical basis for targeting c-Met in the treatment of GC. Methods Ninety-seven patients who underwent curative gastrectomy in our hospital from December 2013 to September 2015 were included in this study. The tissue microarray was constructed by paraffin-embedded tumor tissue of enrolled patients, including 97 GC points and 83 paracancerous points. Then, it was used for c-Met immunohistochemical staining, followed by an immunological H-score. The clinical baseline data and 5-year survival of patients with low and high c-Met expression were compared. Besides, the correlation between the expression of c-Met in tumor tissues and preoperative serum tumor markers was investigated. Finally, multivariate Cox regression analysis was used to explore the survival risk factors of patients. Results c-Met has a high expression rate in GC tissues 64.95% (63/97). The expression of c-Met was significantly different in different clinicopathological stages (p < 0.05); the high expression group also had a higher M stage and clinicopathological stage of GC. The correlation test between the c-Met H-score and CA125 was statistically significant (p = 0.004), indicating a positive correlation. Furthermore, high c-Met expression correlated with poor overall survival (OS) for 5 years (p = 0.005). It was also found that the high expression of c-Met in stage I–II patients was correlative with poor OS for 5 years (p = 0.026), while stage III–IV patients had no statistical significance (p > 0.05). Multivariate Cox regression analysis showed that c-Met might be an independent risk factor for survival 5 years after surgery. Conclusion This study found that the high expression of c-Met in GC tissues was associated with poor 5-year OS in GC patients and was an independent risk factor for 5-year survival after curative gastrectomy. The expression of c-Met in GC tissues was also positively correlated with preoperative serum CA125.
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Affiliation(s)
- Zhengchao Zhang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China.,Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, 730900, China
| | - Lele Miao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China
| | - Song Wang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China
| | - Yang Zhao
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China
| | - Yongqiang Xie
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, 730900, China
| | - Heng Yun
- Department of General Surgery, The Third Affiliated Hospital of Gansu University of Traditional Chinese Medicine, Lanzhou, 730900, China
| | - Zhijian Ren
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China
| | - Guan Wang
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China.,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China
| | - Muzhou Teng
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China. .,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China.
| | - Yumin Li
- Department of General Surgery, Lanzhou University Second Hospital, Lanzhou, 730000, China. .,Key Laboratory of Digestive System Tumors of Gansu Province, Lanzhou, 730000, China.
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18
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Zhang J, Dai J, Lan X, Zhao Y, Yang F, Zhang H, Tang S, Liang G, Wang X, Tang Q. Synthesis, bioevaluation and molecular dynamics of pyrrolo-pyridine benzamide derivatives as potential antitumor agents in vitro and in vivo. Eur J Med Chem 2022; 233:114215. [DOI: 10.1016/j.ejmech.2022.114215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 02/17/2022] [Accepted: 02/19/2022] [Indexed: 11/04/2022]
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19
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Ooki A, Yamaguchi K. The dawn of precision medicine in diffuse-type gastric cancer. Ther Adv Med Oncol 2022; 14:17588359221083049. [PMID: 35281349 PMCID: PMC8908406 DOI: 10.1177/17588359221083049] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Accepted: 01/31/2022] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most common malignancies worldwide. The histology- and morphology-based Lauren classification of GC has been widely used for over 50 years in clinical practice. The Lauren classification divides GC into intestinal and diffuse types, which have distinct etiology, molecular profiles, and clinicopathological features. Diffuse-type GC (DGC) accounts for approximately 30% of GCs. Tumor cells lack adhesion and infiltrate the stroma as single cells or small subgroups, leading to easy dissemination in the abdominal cavity. Clinically, DGC has aggressive traits with a high risk of recurrence and metastasis, which results in unfavorable prognosis. Although systemic chemotherapy is the main therapeutic approach for recurrent or metastatic GC patients, clinical benefits are limited for patients with DGC. Therefore, it is urgent to develop effective therapeutic strategies for DGC patients. Considerable research studies have characterized the molecular and genomic landscape of DGC, of which tight junction protein claudin-18 isoform 2 (CLDN18.2) and fibroblast growing factors receptor-2 isoform IIIb (FGFR2-IIIb) are the most attractive targets because of their close association with DGC. Recently, the impressive results of two phase II FAST and FIGHT trials demonstrate proof-of-concept, suggesting that anti-CLDN18.2 antibody (zolbetuximab) and FGFR2-IIIb antibody (bemarituzumab) are promising approaches for patients with CLDN18.2-positive and FGFR2-IIIb-positive GC, respectively. In this review, we summarize the clinicopathological features and molecular profiles of DGC and highlight a potential therapeutic target based on the findings of pivotal clinical trials.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
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20
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Liao H, Tian T, Sheng Y, Peng Z, Li Z, Wang J, Li Y, Zhang C, Gao J. The Significance of MET Expression and Strategies of Targeting MET Treatment in Advanced Gastric Cancer. Front Oncol 2021; 11:719217. [PMID: 34557411 PMCID: PMC8453156 DOI: 10.3389/fonc.2021.719217] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Accepted: 08/20/2021] [Indexed: 11/18/2022] Open
Abstract
Background Accurate assessment of predictive biomarker expression is critical in patient selection in clinical trials or clinical practice. However, changes in biomarker expression may occur after treatment. The aim of the present study was to evaluate the effects of chemotherapy on MET expression in gastric cancer (GC). Methods MET expression was examined immunohistochemically before and after treatment in 122 patients with unresectable or recurrent GC, and was evaluated according to H-score or the scoring criteria used in the MetMAb trial. MET gene amplification was assessed by chromogenic in situ hybridization (CISH). The antitumor effect of MET targeted therapy was investigated in human gastric cancer cells in vitro and in vivo, and the underlying molecular mechanisms were analyzed by western blot. Results MET expression was associated with Lauren classification as well as tumor differentiation by either scoring system. MET amplification was not associated with clinical characteristics. Of the 71 patients who had paired pre- and post-treatment tumor tissues, 28 patients (39%) were initially positive for MET expression, and 43 (61%) were negative. Twenty-five patients (35%) showed significant changes in MET expression after treatment (P=0.007). Additionally, there was a concomitant overexpression of MET and HER2 in a subset of GC patients. MET inhibitor volitinib could significantly inhibit cell proliferation and xenograft growth in vitro and in vivo in MKN45 cells with MET and phosphorylated MET (pMET) high expressions via suppressing downstream PI3K/Akt and MAPK signaling pathways. Furthermore, combination therapy targeting both MET and HER2 demonstrated a synergistic antitumor activity. Conclusions MET expression is altered post chemotherapy and MET status should be evaluated in real-time. Both MET and pMET expressions might need to be considered for patients suitable for volitinib treatment.
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Affiliation(s)
- Haiyan Liao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
| | - Tiantian Tian
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China.,Department of Oncology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China
| | - Yuling Sheng
- School of Medicine, The Southern University of Science and Technology, Shenzhen, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Zhongwu Li
- Department of Pathology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jingyuan Wang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Yanyan Li
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Cheng Zhang
- Department of Gastrointestinal Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing, China
| | - Jing Gao
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital & Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, China
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21
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Marano L, Marrelli D, Sammartino P, Biacchi D, Graziosi L, Marino E, Coccolini F, Fugazzola P, Valle M, Federici O, Baratti D, Deraco M, Di Giorgio A, Macrì A, Pasqual EM, Framarini M, Vaira M, Roviello F. Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Gastric Cancer with Synchronous Peritoneal Metastases: Multicenter Study of 'Italian Peritoneal Surface Malignancies Oncoteam-S.I.C.O.'. Ann Surg Oncol 2021; 28:9060-9070. [PMID: 34057569 PMCID: PMC8590997 DOI: 10.1245/s10434-021-10157-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 04/29/2021] [Indexed: 12/20/2022]
Abstract
Background The development of multimodality treatment, including cytoreductive surgery (CRS) with heated intraperitoneal chemotherapy (HIPEC), has led to promising results in selected patients with peritoneal disease of gastric origin. The aim of this study was to investigate the short- and long-term outcomes of CRS/HIPEC in the treatment of synchronous peritoneal metastasis in gastric cancer. Methods The Italian Peritoneal Surface Malignancies Oncoteam—S.I.C.O. retrospective registry included patients with synchronous peritoneal malignancy from gastric cancer submitted to gastrectomy with CRS and HIPEC between 2005 and 2018 from 11 high-volume, specialized centers. Results A total of 91 patients with a median age of 58 years (range 26–75) were enrolled. The median overall survival (OS) time for the whole group of patients was 20.2 months (95% confidence interval [CI] 11.8–28.5] and the median recurrence-free survival (RFS) was 7.3 months (95% CI 4–10.6). The completeness of cytoreduction score (CCS) of 0 and Peritoneal Cancer Index (PCI) score of ≤ 6 groups showed a significantly better long-term survival (median OS 40.7 and 44.3 months, respectively) compared with the incomplete resected groups (median OS 10.7 months, p = 0.003) and PCI score of > 6 group (median OS 13.4 months, p = 0.005). A significant difference was observed in the survival rate according to neoadjuvant treatment (untreated patients: 10.7 months, 95% CI 5.1–16.2; treated patients: 35.3 months, 95% CI 2.8–67.8; p = 0.022). Conclusions In referral centers, CRS and HIPEC after neoadjuvant treatment significantly improved survival in selected patients. Patients with a PCI score ≤ 6, complete cytoreduction, negative nodal involvements, and negative cytology had encouraging results, showing a clinically meaningful survival.
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Affiliation(s)
- Luigi Marano
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy.
| | - Daniele Marrelli
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
| | - Paolo Sammartino
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Daniele Biacchi
- Cytoreductive Surgery and HIPEC Unit, Department of Surgery "Pietro Valdoni", Sapienza University of Rome, Rome, Italy
| | - Luigina Graziosi
- General and Emergency Surgery, University of Perugia, Perugia, Italy
| | - Elisabetta Marino
- General and Emergency Surgery, University of Perugia, Perugia, Italy
| | - Federico Coccolini
- General, Emergency and Trauma Surgery Department, Bufalini Hospital, Cesena, Italy.,General, Emergency and Trauma Surgery Department, Pisa University Hospital, Pisa, Italy
| | - Paola Fugazzola
- General, Emergency and Trauma Surgery Department, Bufalini Hospital, Cesena, Italy
| | - Mario Valle
- Department of Digestive Surgery, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Orietta Federici
- Department of Digestive Surgery, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Dario Baratti
- Fondazione IRCCS Istituto Nazionale Dei Tumori di Milano, Peritoneal Surface Malignancies Unit, Milan, Italy
| | - Marcello Deraco
- Fondazione IRCCS Istituto Nazionale Dei Tumori di Milano, Peritoneal Surface Malignancies Unit, Milan, Italy
| | - Andrea Di Giorgio
- Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Antonio Macrì
- Peritoneal Surface Malignancy and Soft Tissue Sarcoma Program, Messina University Medical School Hospital, Messina, Italy
| | - Enrico Maria Pasqual
- Department of Medical Area, University of Udine, Santa Maria della Misericordia University Hospital Udine, Udine, Italy
| | | | - Marco Vaira
- Candiolo Cancer Institute, Unit of Surgical Oncology, FPO-IRCCS, Candiolo, Italy
| | - Franco Roviello
- Department of Medicine, Surgery and Neurosciences, Unit of General Surgery and Surgical Oncology, University of Siena, Siena, Italy
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22
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Razavi ZS, Asgarpour K, Mahjoubin-Tehran M, Rasouli S, Khan H, Shahrzad MK, Hamblin MR, Mirzaei H. Angiogenesis-related non-coding RNAs and gastrointestinal cancer. MOLECULAR THERAPY-ONCOLYTICS 2021; 21:220-241. [PMID: 34095461 PMCID: PMC8141508 DOI: 10.1016/j.omto.2021.04.002] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal (GI) cancers are among the main reasons for cancer death globally. The deadliest types of GI cancer include colon, stomach, and liver cancers. Multiple lines of evidence have shown that angiogenesis has a key role in the growth and metastasis of all GI tumors. Abnormal angiogenesis also has a critical role in many non-malignant diseases. Therefore, angiogenesis is considered to be an important target for improved cancer treatment. Despite much research, the mechanisms governing angiogenesis are not completely understood. Recently, it has been shown that angiogenesis-related non-coding RNAs (ncRNAs) could affect the development of angiogenesis in cancer cells and tumors. The broad family of ncRNAs, which include long non-coding RNAs, microRNAs, and circular RNAs, are related to the development, promotion, and metastasis of GI cancers, especially in angiogenesis. This review discusses the role of ncRNAs in mediating angiogenesis in various types of GI cancers and looks forward to the introduction of mimetics and antagonists as possible therapeutic agents.
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Affiliation(s)
| | - Kasra Asgarpour
- Department of Medicine, University of Western Ontario, London, ON, Canada
| | - Maryam Mahjoubin-Tehran
- Department of Medical Biotechnology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Susan Rasouli
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University Mardan, Mardan, Pakistan
| | - Mohammad Karim Shahrzad
- Department of Internal Medicine and Endocrinology, Shohadae Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein 2028, South Africa
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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23
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Xiang Y, Liang B, Jiang Y, Sun F, Zhao Y, Wu Q, Hu X, Liu Y, Huang Q, Liao W, Yao Z, Li S, Shi M. MET transcriptional regulator/serine peptidase inhibitor kunitz type 1 panel operating through HGF/c-MET axis as a prognostic signature in pan-cancer. Cancer Med 2021; 10:2442-2460. [PMID: 33751856 PMCID: PMC7982633 DOI: 10.1002/cam4.3834] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2020] [Revised: 01/24/2021] [Accepted: 02/10/2021] [Indexed: 12/17/2022] Open
Abstract
Dysregulations in transcription factors (TFs) and their genetic products play important roles in tumorigenesis, tumor progression and metastasis. However, prognostic value of the transcriptional regulatory networks in different cancers has not been investigated in depth. The purpose of our study was to identify and validate a potential predictive signature that combines TFs and their regulatory products in eight solid tumors. We used bioinformatics analysis to identify MET Transcriptional Regulator (MACC1) and Serine Peptidase Inhibitor Kunitz Type 1 (SPINT1) as candidate TFs with the respective downstream regulatory proteins for patient prognosis in pan‐cancer. Subsequent molecular analysis of clinical gastric cancer tissue samples further verified the negative correlation between MACC1 and SPINT1. Further, we showed that mechanistically, MACC1/SPINT1 mediated the pro‐HGF proteolysis and c‐Met phosphorylation in HGF/c‐MET signaling pathway. Kaplan‐Meier plots and receiver operating characteristics analysis revealed that the two‐gene signature combining MACC1 with SPINT1 was effective in predicting survival in all eight cancer cohorts tested. In conclusion, our study clarified the regulatory relationship between MACC1 and SPINT1 in the context of the HGF/c‐MET signaling pathway and determined MACC1/SPINT1 panel as a valuable signature for the prediction of prognosis in patients for multiple solid cancer types.
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Affiliation(s)
- Yi Xiang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bishan Liang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yu Jiang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Fei Sun
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yang Zhao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qijing Wu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xingbin Hu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yajing Liu
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiong Huang
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Wangjun Liao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Zhiqi Yao
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Shaowei Li
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Min Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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24
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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] [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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25
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Zhou Y, Xu X, Wang F, He H, Qi B. Discovery of 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-diethylpiperidine-1-carboxamide as kinase inhibitor for the treatment of colorectal cancer. Bioorg Chem 2020; 106:104511. [PMID: 33272707 DOI: 10.1016/j.bioorg.2020.104511] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2020] [Revised: 10/01/2020] [Accepted: 11/19/2020] [Indexed: 11/18/2022]
Abstract
In this study, a novel series of 4,6,7-trisubstituted quinoline analogues bearing thiazolidinones were designed and synthesized based on our previous study. Among them, the most potent compound 15i, 4-((4-(4-(3-(2-(2,6-difluorophenyl)-4-oxothiazolidin-3-yl)ureido)-2-fluorophenoxy)-6-methoxyquinolin-7-yl)oxy)-N,N-diethylpiperidine-1-carboxamide was identified as a multi-kinase inhibitor. The results of MTT assay revealed in vitro antitumor activities against HT-29 cells of compound 15i with an IC50 value of 0.19 μM which was 14.5-fold more potent than that of Regorafenib. In the cellular context, significant antiproliferation, cytotoxicity and induction of apoptosis on HT-29 cells in a dose- and time-dependent manner were confirmed by IncuCyte live-cell imaging assays. Moreover, compound 15i strongly induced apoptosis by arresting cell cycle into the G2/M phase. No antiproliferation and cytotoxicity against human normal colorectal mucosa epithelial cell FHC was observed at 10.0 μg/mL or lower concentrations which indicated that the toxicity to normal cells of compound 15i was much lower than that of Regorafenib. Based on the above findings, further structural modification will be conducted for the development of more potent kinase inhibitors as anticancer agents.
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Affiliation(s)
- Yuting Zhou
- Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China
| | - Xingwei Xu
- Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China
| | - Fei Wang
- Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China
| | - Huan He
- Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China.
| | - Baohui Qi
- Department of Bioengineering, Zhuhai Campus of Zunyi Medical University, Zhuhai 519041, Guangdong Province, China.
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26
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El Darsa H, El Sayed R, Abdel-Rahman O. MET Inhibitors for the Treatment of Gastric Cancer: What's Their Potential? J Exp Pharmacol 2020; 12:349-361. [PMID: 33116950 PMCID: PMC7547764 DOI: 10.2147/jep.s242958] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/09/2020] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer remains a disease with a dismal prognosis. Extensive efforts to find targetable disease drivers in gastric cancer were implemented to improve patient outcomes. Beyond anti-HER2 therapy, MET pathway seems to be culprit of cancer invasiveness with MET-overexpressing tumors having poorer prognosis. Tyrosine kinase inhibitors targeting the HGF/MET pathway were studied in MET-positive gastric cancer, but no substantial benefit was proven. Some patients responded in early phase trials but later developed resistance. Others failed to show any benefit at all. Etiologies of resistance may entail inappropriate patient selection with a lack of MET detection standardization, tumor alternative pathways, variable MET amplification, and genetic variation. Optimizing MET detection techniques and better understanding the MET pathway, as well as tumor bypass mechanisms, are an absolute need to devise means to overcome resistance using targeted therapy alone, or in combination with other synergistic agents to improve outcomes of patients with MET-positive GC.
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Affiliation(s)
- Haidar El Darsa
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
| | - Rola El Sayed
- Division of Hematology-Oncology, Department of Internal Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Omar Abdel-Rahman
- Division of Medical Oncology, Department of Oncology, Cross Cancer Institute, University of Alberta, Edmonton, Alberta, Canada
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27
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Andreuzzi E, Capuano A, Poletto E, Pivetta E, Fejza A, Favero A, Doliana R, Cannizzaro R, Spessotto P, Mongiat M. Role of Extracellular Matrix in Gastrointestinal Cancer-Associated Angiogenesis. Int J Mol Sci 2020; 21:E3686. [PMID: 32456248 PMCID: PMC7279269 DOI: 10.3390/ijms21103686] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 05/20/2020] [Accepted: 05/21/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal tumors are responsible for more cancer-related fatalities than any other type of tumors, and colorectal and gastric malignancies account for a large part of these diseases. Thus, there is an urgent need to develop new therapeutic approaches to improve the patients' outcome and the tumor microenvironment is a promising arena for the development of such treatments. In fact, the nature of the microenvironment in the different gastrointestinal tracts may significantly influence not only tumor development but also the therapy response. In particular, an important microenvironmental component and a potential therapeutic target is the vasculature. In this context, the extracellular matrix is a key component exerting an active effect in all the hallmarks of cancer, including angiogenesis. Here, we summarized the current knowledge on the role of extracellular matrix in affecting endothelial cell function and intratumoral vascularization in the context of colorectal and gastric cancer. The extracellular matrix acts both directly on endothelial cells and indirectly through its remodeling and the consequent release of growth factors. We envision that a deeper understanding of the role of extracellular matrix and of its remodeling during cancer progression is of chief importance for the development of new, more efficacious, targeted therapies.
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Affiliation(s)
- Eva Andreuzzi
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Alessandra Capuano
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Evelina Poletto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Eliana Pivetta
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Albina Fejza
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Andrea Favero
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Roberto Doliana
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Renato Cannizzaro
- Department of Clinical Oncology, Experimental Gastrointestinal Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy;
| | - Paola Spessotto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
| | - Maurizio Mongiat
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy; (E.A.); (A.C.); (E.P.); (E.P.); (A.F.); (A.F.); (R.D.); (P.S.)
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28
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Andreuzzi E, Fejza A, Capuano A, Poletto E, Pivetta E, Doliana R, Pellicani R, Favero A, Maiero S, Fornasarig M, Cannizzaro R, Iozzo RV, Spessotto P, Mongiat M. Deregulated expression of Elastin Microfibril Interfacer 2 (EMILIN2) in gastric cancer affects tumor growth and angiogenesis. Matrix Biol Plus 2020; 6-7:100029. [PMID: 33543026 PMCID: PMC7852313 DOI: 10.1016/j.mbplus.2020.100029] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2019] [Revised: 02/13/2020] [Accepted: 02/13/2020] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is a frequent human tumor and often a lethal disease. Targeted therapy for gastric carcinomas is far behind vis-à-vis other solid tumors, primarily because of the paucity of cancer-driving mutations that could be efficiently and specifically targeted by current therapy. Thus, there is a need to discover actionable pathways/proteins and new diagnostic and prognostic biomarkers. In this study, we explored the role of the extracellular matrix glycoprotein EMILIN2, Elastin Microfibril Interfacer 2, in a cohort of gastric cancer patients. We discovered that EMILIN2 expression was consistently suppressed in gastric cancer and high expression levels of this glycoprotein were linked to abnormal vascular density. Furthermore, we found that EMILIN2 had a dual effect on gastric carcinoma cells: on one hand, it decreased tumor cell proliferation by triggering apoptosis, and on the other hand, it evoked the production of a number of cytokines involved in angiogenesis and inflammation, such as IL-8. Collectively, our findings posit EMILIN2 as an important onco-regulator exerting pleiotropic effects on the gastric cancer microenvironment.
EMILIN2 is localized in the gastric lamina propria and its expression is down-regulated in gastric cancer. High levels of EMILIN2 associate with elevated vascular density. EMILIN2 impairs the proliferation of gastric cancer cells by evoking apoptosis. Surprisingly, EMILIN2 triggers the expression of pro-angiogenic and pro-inflammatory cytokines.
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Key Words
- 5-FU, 5-fluorouracil
- Angiogenesis
- CAFCA, Centrifugal Assay for Fluorescence-based Cell Adhesion
- CD31, cluster of differentiation 31 also known as PECAM-1
- ECM, extracellular matrix
- EGFR, epidermalgrowth factor receptor
- EMILIN 2, Elastin Microfibril Interfacer 2
- Extracellular matrix
- GC, gastric cancer
- Gastric cancer
- HER2, human epidermal growth factor receptor 2
- IGFBP2, insulin growth factor-binding protein 2
- Inflammation
- PFS, progression free survival
- Serpin 1, serine protease inhibitor 1
- Tumor microenvironment
- VEGFA, vascular endothelial growth factor A
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Affiliation(s)
- Eva Andreuzzi
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Albina Fejza
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Alessandra Capuano
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Evelina Poletto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Eliana Pivetta
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Roberto Doliana
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Rosanna Pellicani
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Andrea Favero
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Stefania Maiero
- Department of Clinical Oncology, Experimental Gastrointestinal, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Mara Fornasarig
- Department of Clinical Oncology, Experimental Gastrointestinal, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Renato Cannizzaro
- Department of Clinical Oncology, Experimental Gastrointestinal, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Renato V Iozzo
- Department of Pathology, Anatomy, and Cell Biology and the Cancer Cell Biology and Signaling Program, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, USA
| | - Paola Spessotto
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - Maurizio Mongiat
- Department of Research and Diagnosis, Division of Molecular Oncology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
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29
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Li J, Li J, Zhang J, Shi J, Ding S, Liu Y, Chen Y, Liu J. Design, Synthesis and Biological Evaluation of Novel 4-phenoxypyridine Derivatives Containing Semicarbazones Moiety as Potential c-Met Kinase Inhibitors. Anticancer Agents Med Chem 2020; 20:559-570. [PMID: 31893997 DOI: 10.2174/1871520620666200101143307] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2019] [Revised: 11/28/2019] [Accepted: 12/04/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND The Hepatocyte Growth Factor Receptor (HGFR) c-Met is over-expressed and/or mutated in various human tumor types. Dysregulation of c-Met/HGF signaling pathway affects cell proliferation, survival and motility, leading to tumor growth, angiogenesis, and metastasis. Therefore, c-Met has become an attractive target for cancer therapy. OBJECTIVE This study is aimed to evaluate a new series of 4-phenoxypyridine derivatives containing semicarbazones moiety for its cytotoxicity. METHODS A series of novel 4-phenoxypyridines containing semicarbazone moieties were synthesized and evaluated for their in vitro cytotoxic activities against MKN45 and A549 cancer cell lines and some selected compounds were further examined for their inhibitory activity against c-Met kinase. In order to evaluate the mechanism of cytotoxic activity of compound 24, cell cycle analysis, Annexin V/PI staining assay, AO/EB assay, wound-healing assay and docking analysis with c-Met were performed. RESULTS The results indicated that most of the compounds showed moderate to good antitumor activity. The compound 28 showed well cytotoxic activity against MKN45 and A549 cell lines with IC50 values of 0.25μM and 0.67μM, respectively. Compound 24 showed good activity on c-Met and its IC50 value was 0.093μM. CONCLUSION Their preliminary Structure-Activity Relationships (SARs) studies indicated that electronwithdrawing groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Treatments of MKN45 cells with compound 24 resulted in cell cycle arrest in G2/M phase and induced apoptosis in a dose-dependent manner. In addition, AO/EB assays indicated 24 induced dose-dependent apoptosis of A549 and MKN45 cells. Wound-healing assay results indicated that compound 24 strongly inhibited A549 cell motility.
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Affiliation(s)
- Jun Li
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China
| | - Jie Li
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China
| | - Jiaojiao Zhang
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China
| | - Jiantao Shi
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China
| | - Shi Ding
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China
| | - Yajing Liu
- Key Laboratory of Structure-Based Drug Design and Discovery (Shenyang Pharmaceutical University), Ministry of Education, 103 Wenhua Road, Shenhe District, Shenyang 110016, China
| | - Ye Chen
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China.,API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, China
| | - Ju Liu
- College of Pharmacy, Key Laboratory of New Drug Research and Development of Liaoning Province, Liaoning University, Shenyang 110036, China.,API Engineering Technology Research Center of Liaoning Province, 66 Chongshan Road, Huanggu District, Shenyang 110036, China
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Clark JW, Camidge DR, Kwak EL, Maki RG, Shapiro GI, Chen I, Tan W, Randolph S, Christensen JG, Ozeck M, Tang Y, Wilner KD, Salgia R. Dose-escalation trial of the ALK, MET & ROS1 inhibitor, crizotinib, in patients with advanced cancer. Future Oncol 2019; 16:4289-4301. [PMID: 31778074 DOI: 10.2217/fon-2019-0653] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Aim: This first-in-human, dose-finding study evaluated safety, pharmacokinetics and pharmacodynamics of crizotinib and established a recommended Phase II dose (RP2D) among patients with advanced solid malignancies. Patients & methods: Patients received oral crizotinib in a 3 + 3 dose escalation design. Results: Thirty-six patients received crizotinib (50 mg once daily-300 mg twice daily); maximum tolerated dose (and RP2D) was 250 mg twice daily. Most patients (89%) experienced ≥1 treatment-related adverse event. Three patients had grade 3 dose-limiting toxicities: alanine aminotransferase increased (n = 1) and fatigue (n = 2). Generally, an increase in soluble MET was found with increasing crizotinib concentrations. Conclusion: Crizotinib demonstrated a favorable safety profile. The observed pharmacodynamic effect on soluble MET provide evidence for targeted MET inhibition by crizotinib. Clinicaltrials. gov identifier: NCT00585195.
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Affiliation(s)
- Jeffrey W Clark
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - D Ross Camidge
- Division of Medical Oncology, University of Colorado Comprehensive Cancer Center, Aurora, CO 80045, USA
| | - Eunice L Kwak
- Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Robert G Maki
- Don Monti Division of Medical Oncology & Hematology, Northwell Cancer Institute & Cold Spring Harbor Laboratory, Lake Success, NY 11724, USA
| | - Geoffrey I Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
| | - Isan Chen
- Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA
| | - Weiwei Tan
- Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA
| | - Sophia Randolph
- Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA
| | | | - Mark Ozeck
- Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA
| | - Yiyun Tang
- Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA
| | - Keith D Wilner
- Oncology Clinical Development, Pfizer Oncology, La Jolla, CA 92121, USA
| | - Ravi Salgia
- Department of Medical Oncology & Therapeutics Research, The City of Hope, Duarte, CA 91010, USA
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Wang Y, Xiao H, Wang C, Wu H, He H, Yao C, Cui J, Li W. M-phase phosphoprotein 8 promotes gastric cancer growth and metastasis via p53/Bcl-2 and EMT-related signaling pathways. J Cell Biochem 2019; 121:2330-2342. [PMID: 31692032 DOI: 10.1002/jcb.29456] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Accepted: 10/10/2019] [Indexed: 12/29/2022]
Abstract
BACKGROUND The main issue of this study is to demonstrate whether M-phase phosphoprotein 8 (MPP8) affect gastric tumor growth and metastasis. METHODS Retrospective study was proceeded in 280 patients' surgical specimens with different disease stages. Loss-of-function assays, including 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide, flow cytometry, and transwell assays were performed to evaluate the biological function of MPP8 in gastric cancer cells. Apoptosis and metastasis relative biomarkers were measured by quantitative real-time polymerase chain reaction and Western blot analysis. RESULTS Compared with normal adjacent tissues, obviously elevated MPP8 expression was found in gastric cancer tissues. Elevated MPP8 expression was associated with male sex (vs female sex), intermediate differentiation (vs poorly differentiated cancer), and later stage (vs earlier stage). Furthermore, MPP8 overexpression in tumor tissues was marginally associated with a poor prognosis, with a significant relationship between MPP8 overexpression and prognosis among patients with poorly differentiated gastric cancer. Inhibition of MPP8 in these cells significantly suppressed proliferation and colony formation, promoted apoptosis, and repressed invasion. Furthermore, silencing of MPP8 remarkably increased apoptosis-related proteins (p53, Bax, and PARP) expression, but downregulated Bcl-2 expression. Silencing of MPP8 also decreased the expression of metastasis pathway-related proteins (N-cadherin and vimentin), and as well as the levels of anti-oncogene ZEB1, MET, and KRAS mRNA. CONCLUSION Our findings demonstrated that MPP8 might be an oncogene by positively regulating gastric cancer cell function through the p53/Bcl-2 and epithelial to mesenchymal transition-related signaling pathways.
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Affiliation(s)
- Yizhuo Wang
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Huijie Xiao
- Department of Gastrointestinal Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Chang Wang
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Haitao Wu
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Hua He
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Cheng Yao
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Jiuwei Cui
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
| | - Wei Li
- Department of Cancer Center, First Hospital of Jilin University, Changchun, China
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Evaluation of Intratumoral and Intertumoral Heterogeneity of MET Protein Expression in Gastric Cancer. Appl Immunohistochem Mol Morphol 2019; 26:445-453. [PMID: 28968267 DOI: 10.1097/pai.0000000000000448] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Tumor heterogeneity of a target molecule could contribute to failure of the targeted therapy. We investigated the heterogeneity of MET expression within same primary gastric cancer (GC) and between primary and corresponding secondary GC lesions using immunohistochemistry (IHC). Intratumoral heterogeneity was defined as discordant MET status among 3 tissue microarray cores (3 different areas of same tumor). IHC 3+ was considered positive for MET overexpression. MET overexpression was observed in 2.7% (50/1869) of all examined cores and 5.3% (33/623) of primary GCs. When we compared MET IHC results between 3 cores from each tumor, intratumoral heterogeneity was identified (65.0% in total 623 cases; 84.4% in 480 cases with any staining intensity; 84.9% in 251 cases with moderate to strong intensity; 90.9% in 33 cases with strong intensity). Of 33 MET-overexpressed GCs, the average proportion of strongly stained area was 19.6% in the whole sections. Of 269 cases with primary GC and regional lymph node metastasis, 17 (6.3%) showed MET positivity in which 9 (52.9%) were discordant (negative conversion). In 123 cases with primary and corresponding local recurrent/distant metastatic GC, 3 (2.4%) showed MET positivity in which 2 (66.7%) were discordant (positive conversion). In the survival analysis, MET IHC 3+ in lymph node metastases was an independent negative prognostic factor for overall survival. We found that MET overexpression is uncommon and highly heterogeneous in GC. This severe heterogeneity of MET status should be considered in tissue sampling and development of biomarkers for anti-MET therapy.
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Liu J, Li S, Chen S, Chen S, Geng Q, Xu D. c‐Met‐dependent phosphorylation of RhoA plays a key role in gastric cancer tumorigenesis. J Pathol 2019; 249:126-136. [DOI: 10.1002/path.5287] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2018] [Revised: 03/24/2019] [Accepted: 04/29/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Jianjun Liu
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
| | - Shun Li
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
| | - Shangxiang Chen
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
| | - Shuai Chen
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
| | - Qirong Geng
- Department of Medical Oncology Fudan University Shanghai Cancer Center Shanghai PR China
| | - Dazhi Xu
- State Key Laboratory of Oncology in South PR China Collaborative Innovation Center for Cancer Medicine Guangzhou PR China
- Department of Gastric Surgery Sun Yat‐Sen University Cancer Center Guangzhou PR China
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Chen L, Shi Y, Zhu X, Guo W, Zhang M, Che Y, Tang L, Yang X, You Q, Liu Z. IL‑10 secreted by cancer‑associated macrophages regulates proliferation and invasion in gastric cancer cells via c‑Met/STAT3 signaling. Oncol Rep 2019; 42:595-604. [PMID: 31233202 PMCID: PMC6610037 DOI: 10.3892/or.2019.7206] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 05/30/2019] [Indexed: 12/12/2022] Open
Abstract
Gastric cancer is one of the most common types of human cancer, and it is additionally one of the leading causes of cancer-associated mortality worldwide. Previous studies have suggested that interleukin (IL)-10 may contribute to the pathogenesis of gastric cancer. However, the underlying mechanisms remain unclear. In the present study, it was observed that the expression of IL-10 was significantly upregulated in gastric tumor tissues and serum samples of patients with gastric cancer. Furthermore, IL-10 was increased in the cell culture supernatant of cancer-associated macrophages (CAMs). Treatment with cell culture supernatant from CAMs induced a significant increase in proliferation and migration, while it suppressed apoptosis, in MGC-803 and BGC-823 gastric cancer cells. Notably, application of an inhibitory IL-10 antibody partially blocked the cell culture supernatant of CAM-induced oncogenic effects. RNA-sequencing analysis was then performed to identify the differentially expressed genes in MGC-803 cells treated with IL-10. Based on the sequencing results and in vitro analysis, it was demonstrated that IL-10-induced carcinogenic behaviors in MGC-803 cells were potentially mediated by activation of the c-Met/STAT3 signaling pathway. In conclusion, the present results demonstrated that IL-10 secreted by CAMs may be involved in the pathogenesis of gastric cancer, suggesting that IL-10 may serve as a potential therapeutic target for the treatment of gastric cancer.
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Affiliation(s)
- Ling Chen
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Yuntao Shi
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Xiaojuan Zhu
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Weiwei Guo
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Mingjiong Zhang
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Ying Che
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Lijuan Tang
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Xiaozhong Yang
- Department of Gastroenterology, The Affiliated Huai'an No. 1 People's Hospital of Nanjing Medical University, Huai'an, Jiangsu 223300, P.R. China
| | - Qiang You
- Department of Biotherapy, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
| | - Zheng Liu
- Institute of Digestive Endoscopy and Medical Center for Digestive Disease, The Second Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu 210011, P.R. China
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Lin X, Peng Z, Wang X, Zou J, Chen D, Chen Z, Li Z, Dong B, Gao J, Shen L. Targeting autophagy potentiates antitumor activity of Met-TKIs against Met-amplified gastric cancer. Cell Death Dis 2019; 10:139. [PMID: 30760701 PMCID: PMC6374362 DOI: 10.1038/s41419-019-1314-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2018] [Revised: 12/05/2018] [Accepted: 12/20/2018] [Indexed: 12/19/2022]
Abstract
Met tyrosine kinase inhibitors (Met-TKIs) subjected to ongoing clinical trials are a promising option for Met-amplified gastric cancer (GC), but how to optimize their antitumor activity especially with combination schemes remains unclear. Since autophagy is known to be initiated by Met-TKIs, we investigated its underlying mechanisms and therapeutic potentials of Met-TKIs combined with autophagy inhibitors against Met-amplified GC. As expected, four Met-TKIs induced autophagy in Met-amplified GC cells marked by p62 degradation, LC3-II accumulation and increased LC3-positive puncta. Autophagy flux activation by Met-TKIs was further validated with combined lysosomal inhibitors, bafilomycin A1 (Baf A1) and hydroxychloroquine (HCQ). Molecular investigations reveal that autophagy induction along with mTOR and ULK1 de-phosphorylation upon Met-TKI treatment could be relieved by hepatocyte growth factor (HGF) and mTOR agonist MHY1485 (MHY), suggesting that autophagy was initiated by Met-TKIs via Met/mTOR/ULK1 cascade. Intriguingly, Met-TKIs further suppressed cell survival and tumor growth in the presence of autophagy blockade in Met-amplified GC preclinical models. Thus, these findings indicate Met/mTOR/ULK1 cascade responsible for Met-TKI-mediated autophagy and Met-TKIs combined with autophagy inhibitors as a promising choice to treat Met-amplified GC.
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Affiliation(s)
- Xiaoting Lin
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhi Peng
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Xiaojuan Wang
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jianling Zou
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Dongshao Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zuhua Chen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Zhongwu Li
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Bin Dong
- Department of Pathology, Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, 100142, China
| | - Jing Gao
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
| | - Lin Shen
- Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China.
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Electrostatic explanation of D1228V/H/N-induced c-Met resistance and sensitivity to type I and type II kinase inhibitors in targeted gastric cancer therapy. J Mol Model 2019; 25:13. [DOI: 10.1007/s00894-018-3893-3] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2018] [Accepted: 12/04/2018] [Indexed: 01/28/2023]
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Zhang J, Fa X, Zhang Q. MicroRNA‑206 exerts anti‑oncogenic functions in esophageal squamous cell carcinoma by suppressing the c‑Met/AKT/mTOR pathway. Mol Med Rep 2018; 19:1491-1500. [PMID: 30569129 PMCID: PMC6390054 DOI: 10.3892/mmr.2018.9775] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 10/12/2018] [Indexed: 12/27/2022] Open
Abstract
Increasing evidence suggests that the dysregulation of microRNAs (miRNAs) has an important role in the progression of human cancer, including ESCC. However, the exact functions and mechanisms of miRNAs in ESCC remain largely unclear. The aim of the present study was to investigate the expression and biological functions of miRNAs in ESCC and reveal the underlying molecular mechanisms. miRNA microarray and reverse transcription-quantitative polymerase chain reaction analyses were performed, which identified and confirmed that miR-206 was significantly downregulated in ESCC tissues and cell lines. Its low expression was associated with lymph node metastasis, advanced TNM stage and N classification, as well as poorer overall survival in patients with ESCC. CCK-8 and flow cytometry assays demonstrated that ectopic miR-206 expression inhibited ESCC cell proliferation and induced cell apoptosis. In addition, MET proto-oncogene, receptor tyrosine kinase (c-Met), a well-known oncogene, was a direct target of miR-206. An inverse correlation between the levels of miR-206 and c-Met mRNA in ESCC tissue samples was confirmed. Notably, c-Met overexpression inhibited the effects of miR-206 on the proliferation and apoptosis of ESCC cells. Additionally, it was confirmed that the tumor-suppressive functions of miR-206 may have contributed to the inactivation of the c-Met/protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) signaling pathway. In conclusion, the findings of the present study suggested that miR-206 exerts its anti-cancer functions via the c-Met/AKT/mTOR signaling pathway, providing a novel candidate prognostic factor and a potential therapeutic target in ESCC.
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Affiliation(s)
- Jin Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Xianen Fa
- Department of Cardiac Surgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
| | - Qingyong Zhang
- Department of Thoracic Surgery, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450014, P.R. China
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Loss of Multimerin-2 and EMILIN-2 Expression in Gastric Cancer Associate with Altered Angiogenesis. Int J Mol Sci 2018; 19:ijms19123983. [PMID: 30544909 PMCID: PMC6321373 DOI: 10.3390/ijms19123983] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 12/06/2018] [Indexed: 01/25/2023] Open
Abstract
Gastric cancer is a deadly tumor and a relatively common disease worldwide. Surgical resection and chemotherapy are the main clinical options to treat this type of disease, however the median overall survival rate is limited to one year. Thus, the development of new therapies is a highly necessary clinical need. Angiogenesis is a promising target for this tumor type, however clinical trials with the use of anti-angiogenic drugs have so far not met expectations. Therefore, it is important to better characterize the expression of molecules whose expression levels may impact on the efficacy of the treatments. In this study the characteristics of the gastric tumor associated blood vessels were first assessed by endomicroscopy. Next, we analyzed the expression of Multimerin-2, EMILIN-2 and EMILIN-1, three molecules of the EMI Domain ENdowed (EDEN) protein family. These molecules play important functions in the tumor microenvironment, affecting cancer progression both directly and indirectly impinging on angiogenesis and lymphangiogenesis. All the molecules were highly expressed in the normal mucosa whereas in a number of patients their expression was altered. We consider that better characterizing the gastric tumor microenvironment and the quality of the vasculature may achieve effective patient tailored therapies.
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39
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Zhao R, Zhang T, Xi W, Sun X, Zhou L, Guo Y, Zhao C, Bao Y. Human chorionic gonadotropin promotes cell proliferation through the activation of c-Met in gastric cancer cells. Oncol Lett 2018; 16:4271-4278. [PMID: 30197669 PMCID: PMC6126336 DOI: 10.3892/ol.2018.9215] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2015] [Accepted: 06/15/2018] [Indexed: 12/14/2022] Open
Abstract
Hormones and their receptors affect the development process of gastric cancer. Previous studies have revealed that human chorionic gonadotropin (hCG) is expressed in gastric cancer tissue. However, the mechanism by which hCG exerts its effects on gastric cancer cells had not been reported. In the present study, the expression of hCG and its receptor was detected in gastric cancer tissues and para-carcinoma tissues of 62 patients with gastric carcinoma. Following the treatment of gastric cancer cells SGC-7901 with hCG, a cell counting kit-8 assay, flow cytometry, a colony formation assay and a xenograft tumor model in nude mice were used to detect the effect of hCG on cell proliferation; and the expression of c-Met was determined by western blot analysis. The expression of hCG and its receptor were significantly higher in gastric cancer tissues compared with that of the matched para-carcinoma tissue (P<0.01). Proliferation of SGC-7901 cells treated with hCG was significant higher and the number of cells at the G2/M phase of the cell cycle increased compared with the control cells. Hepatocyte growth factor transmembrane protein receptor expression was increased in hCG-treated cells compared with the control cells, which relies on the protein kinase A signaling pathway. The present study revealed the potential function of hCG in the development of gastric cancer, suggesting that hCG may be a molecular marker and potential drug target in gastric cancer.
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Affiliation(s)
- Rui Zhao
- Department of Endoscopy Center, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, P.R. China
| | - Tongtong Zhang
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, P.R. China
| | - Weidong Xi
- Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, P.R. China
| | - Xiaobin Sun
- Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, P.R. China
| | - Lingxiao Zhou
- Department of Endoscopy Center, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, P.R. China
| | - Yuanbiao Guo
- Medical Research Center, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, P.R. China
| | - Cong Zhao
- Department of Gastroenterology, The Third People's Hospital of Chengdu, Chengdu, Sichuan 610031, P.R. China
| | - Yu Bao
- Department of Endoscopy Center, Sichuan Cancer Hospital, Chengdu, Sichuan 610041, P.R. China
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Khandia R, Pattnaik B, Rajukumar K, Pateriya A, Bhatia S, Murugkar H, Prakash A, Pradhan HK, Dhama K, Munjal A, Joshi SK. Anti-proliferative role of recombinant lethal toxin of Bacillus anthracis on primary mammary ductal carcinoma cells revealing its therapeutic potential. Oncotarget 2018; 8:35835-35847. [PMID: 28415766 PMCID: PMC5482621 DOI: 10.18632/oncotarget.16214] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2017] [Accepted: 03/07/2017] [Indexed: 12/11/2022] Open
Abstract
Bacillus anthracis secretes three secretary proteins; lethal factor (LF), protective antigen (PA) and edema factor (EF). The LF has ability to check proliferation of mammary tumors, chiefly depending on mitogen activated protein kinase (MAPK) signaling pathway. Evaluation of therapeutic potential of recombinant LF (rLF), recombinant PA (rPA) and lethal toxin (rLF + rPA = LeTx) on the primary mammary ductal carcinoma cells revealed significant (p < 0.01) reduction in proliferation of tumor cells with mean inhibition indices of 28.0 ± 1.37% and 19.6 ± 1.47% respectively. However, treatment with rPA alone had no significant anti-proliferative effect as evident by low mean inhibition index of 3.4 ± 3.87%. The higher inhibition index observed for rLF alone as compared to LeTx is contrary to the existing knowledge on LF, which explains the requirement of PA dependent endocytosis for its enzymatic activity. Therefore, the plausible existence of PA independent mode of action of LF including direct receptor mediated endocytosis or modulation of signal transduction cascade via unknown means is hypothesized. In silico protein docking analysis of other cellular receptors for any plausibility to play the role of receptor for LF revealed c-Met receptor showing strongest affinity for LF (H bond = 19; Free energy = −773.96), followed by nerve growth factor receptor (NGFR) and human epidermal growth factor receptor (HER)-1. The study summarizes the use of rLF or LeTx as therapeutic molecule against primary mammary ductal carcinoma cells and also the c-Met as potential alternative receptor for LF to mediate and modulate PA independent signal transduction.
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Affiliation(s)
- Rekha Khandia
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India.,Department of Biochemistry and Genetics, Barkatullah University, Bhopal, Madhya Pradesh, India
| | - Bramhadev Pattnaik
- Project Directorate on Foot and Mouth Disease, Mukteswar, Uttarakhand, India
| | | | - Atul Pateriya
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
| | - Sandeep Bhatia
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
| | - Harshad Murugkar
- ICAR-National Institute of High Security Animal Diseases, Bhopal, Madhya Pradesh, India
| | - Anil Prakash
- Department of Microbiology, Barkatullah University, Bhopal, Madhya Pradesh, India
| | - Hare Krishna Pradhan
- Ex-Avian Influenza National Consultant, Indian Office of WHO Consultant, Bhartiya Kala Kendra, New Delhi, India
| | - Kuldeep Dhama
- Division of Pathology, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly Uttar Pradesh, India
| | - Ashok Munjal
- Department of Biochemistry and Genetics, Barkatullah University, Bhopal, Madhya Pradesh, India
| | - Sunil K Joshi
- Cellular Immunology Laboratory, Frank Reidy Research Center of Bioelectrics, College of Health Sciences, Old Dominion University Norfolk, VA USA
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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: 753] [Impact Index Per Article: 107.6] [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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Kashyap MK, Abdel-Rahman O. Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma. Mol Cancer 2018. [PMID: 29455652 DOI: 10.1186/s12943-018-0790-4,] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Esophageal cancer is one of the most common types of cancer, which is a leading cause of cancer-related death worldwide. Based on histological behavior, it is mainly of two types (i) Esophageal squamous cell carcinoma (ESCC), and (ii) esophageal adenocarcinoma (EAD or EAC). In astronomically immense majority of malignancies, receptor tyrosine kinases (RTKs) have been kenned to play a consequential role in cellular proliferation, migration, and metastasis of the cells. The post-translational modifications (PTMs) including phosphorylation of tyrosine (pY) residue of the tyrosine kinase (TK) domain have been exploited for treatment in different malignancies. Lung cancer where pY residues of EGFR have been exploited for treatment purpose in lung adenocarcinoma patients, but we do not have such kind of felicitously studied and catalogued data in ESCC patients. Thus, the goal of this review is to summarize the studies carried out on ESCC to explore the role of RTKs, tyrosine kinase inhibitors, and their pertinence and consequentiality for the treatment of ESCC patients.
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Affiliation(s)
- Manoj Kumar Kashyap
- School of Life and Allied Health Sciences, Glocal University, Saharanpur, UP, 247121, India. .,Department of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh, India.
| | - Omar Abdel-Rahman
- Clinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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Kashyap MK, Abdel-Rahman O. Expression, regulation and targeting of receptor tyrosine kinases in esophageal squamous cell carcinoma. Mol Cancer 2018; 17:54. [PMID: 29455652 PMCID: PMC5817798 DOI: 10.1186/s12943-018-0790-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Accepted: 02/01/2018] [Indexed: 02/07/2023] Open
Abstract
Esophageal cancer is one of the most common types of cancer, which is a leading cause of cancer-related death worldwide. Based on histological behavior, it is mainly of two types (i) Esophageal squamous cell carcinoma (ESCC), and (ii) esophageal adenocarcinoma (EAD or EAC). In astronomically immense majority of malignancies, receptor tyrosine kinases (RTKs) have been kenned to play a consequential role in cellular proliferation, migration, and metastasis of the cells. The post-translational modifications (PTMs) including phosphorylation of tyrosine (pY) residue of the tyrosine kinase (TK) domain have been exploited for treatment in different malignancies. Lung cancer where pY residues of EGFR have been exploited for treatment purpose in lung adenocarcinoma patients, but we do not have such kind of felicitously studied and catalogued data in ESCC patients. Thus, the goal of this review is to summarize the studies carried out on ESCC to explore the role of RTKs, tyrosine kinase inhibitors, and their pertinence and consequentiality for the treatment of ESCC patients.
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Affiliation(s)
- Manoj Kumar Kashyap
- grid.449790.7School of Life and Allied Health Sciences, Glocal University, Saharanpur, UP 247121 India
- grid.430140.2Department of Applied Sciences and Biotechnology, Shoolini University of Biotechnology and Management Sciences, Solan, Himachal Pradesh India
| | - Omar Abdel-Rahman
- 0000 0004 0621 1570grid.7269.aClinical Oncology Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt
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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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Doi T, Yamaguchi K, Komatsu Y, Muro K, Nishina T, Nakajima TE, Tang R, Yang H, Zhang Y, Jung AS, Ang A, Yasui H. A Phase 1/1b tolerability study of rilotumumab alone or in combination with cisplatin and capecitabine in Japanese patients with gastric cancer. Jpn J Clin Oncol 2018; 47:1002-1009. [PMID: 28973403 DOI: 10.1093/jjco/hyx114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2017] [Accepted: 08/09/2017] [Indexed: 12/11/2022] Open
Abstract
Objective To evaluate the safety (including adverse events and dose-limiting toxicities [DLTs]), tolerability, pharmacokinetics and antitumor activity of the investigational MET inhibitor rilotumumab alone in patients with advanced solid tumors (Part 1) or in combination with cisplatin plus capecitabine (CX) in patients with MET-positive advanced gastric or gastroesophageal junction cancer (Part 2). Methods Adult patients received 10 or 20 mg/kg intravenous (IV) rilotumumab every 2 weeks (Part 1) or 15 mg/kg IV rilotumumab every 3 weeks plus 80 mg/m2 cisplatin on Day 1 and 1000 mg/m2 capecitabine twice daily on Days 1-14 of every 21-day cycle (Part 2). Results Nine patients enrolled in Part 1; 12 patients enrolled in Part 2. One DLT occurred (Grade 3 decreased appetite and stomatitis [Part 2]). Adverse events related to any treatment occurred in 17 patients (81%) and were Grade ≥3 in nine patients (43%). Rilotumumab pharmacokinetics appeared linear, and exposure was unaffected by CX. No patient who received rilotumumab monotherapy in Part 1 had a response. In Part 2, five of eight patients (63%) with measureable disease at baseline had a partial response and two patients (25%) had stable disease; median (95% CI) progression-free survival was 7.0 (2.4-15.4) months; overall survival was 18.2 (5.6-20.4) months. Conclusions In combination with CX, rilotumumab appeared tolerable and showed antitumor activity in Japanese patients with MET-positive gastric/gastroesophageal junction cancer. However, owing to the results of recent Phase 3 trials of MET inhibitors (including rilotumumab), further development of rilotumumab in this setting is not being pursued. ClinicalTrials.gov Identifier: NCT01791374.
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Affiliation(s)
- Toshihiko Doi
- National Cancer Center Hospital East, Kashiwa, Chiba
| | - Kensei Yamaguchi
- Saitama Cancer Center, Kita Adachi-gun, Saitama.,Cancer Institute Hospital of Japanese Foundation for Cancer Research, Ariake, Tokyo
| | | | - Kei Muro
- Aichi Cancer Center Hospital, Nagoya
| | | | | | - Rui Tang
- Amgen Inc., Thousand Oaks, CA, USA
| | - Hui Yang
- Amgen Inc., Thousand Oaks, CA, USA
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Parikh PK, Ghate MD. Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur J Med Chem 2018; 143:1103-1138. [DOI: 10.1016/j.ejmech.2017.08.044] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 08/03/2017] [Accepted: 08/21/2017] [Indexed: 12/17/2022]
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He YM, Yu C, Li WB, Li ZP, Xu N. Evaluation of short-term effectiveness of eight targeted agents combined with chemotherapy for treating esophageal-gastric junction adenocarcinoma: A network meta-analysis. J Cell Biochem 2018; 119:1183-1192. [PMID: 28708307 DOI: 10.1002/jcb.26288] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2017] [Accepted: 07/12/2017] [Indexed: 12/18/2022]
Abstract
This study aimed to evaluate the short-term effectiveness of eight targeted agents (ramucirumab, bevacizumab, rilotumumab, panitumumab, cetuximab, trebananib, trastuzumab, matuzumab) plus chemotherapy in esophageal-gastric junction adenocarcinoma (EGJA) by a network meta-analysis (NMA). PubMed, Embase, and Cochrane Library databases were systematically retrieved for randomized clinical trials (RCTs) concerning targeted agents plus chemotherapy in the treatment of EGJA. This NMA combined both direct and indirect evidence to evaluate odds ratio (OR) and to draw the surface under the cumulative ranking curve (SUCRA). In total 11 RCTs with 3649 EGJA patients (1907 patients treated with targeted agents plus chemotherapy were regarded as the case group, and 1742 patients with placebo plus chemotherapy were assigned into the control group) were enrolled in this study. Targeted agents in terms of stable disease (SD), partial response (PR), disease control rate (DCR), and overall response ratio (ORR) with the SUCRA values of 0.838, 0.807, 0.934, and 0.793, respectively. Cetuximab and trastuzumab, with the SUCRA values of 0.884 and 0.758, came on top as the best outcomes for treating EGJA in terms of progressive disease (PD) and complete response (CR). Cluster analysis results indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA. Our findings indicated that ramucirumab plus chemotherapy might be the optimal treatment for EGJA amongst the nine treatment regimens, which provided clinical guidance for clinicians in the treatment of EGJA.
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Affiliation(s)
- Yong-Ming He
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Chen Yu
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Wei-Bing Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Zhi-Peng Li
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - Nan Xu
- Department of Integrated Traditional Chinese and Western Medicine, Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
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Farran B, Müller S, Montenegro RC. Gastric cancer management: Kinases as a target therapy. Clin Exp Pharmacol Physiol 2018; 44:613-622. [PMID: 28271563 DOI: 10.1111/1440-1681.12743] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 02/19/2017] [Accepted: 02/20/2017] [Indexed: 12/16/2022]
Abstract
The molecular diagnostics revolution has reshaped the practice of oncology by facilitating the identification of genetic, epigenetic and proteomic modifications correlated with cancer, thus delineating 'oncomaps' for various cancer types. These advances have enhanced our understanding of gastric cancer, one of the most fatal diseases worldwide, and culminated in the approval of novel molecular therapies such as trastuzumab. Gastric tumours display recurrent aberrations in key kinase oncogenes such as Her2, epidermal growth factor receptor (EGFR), PI3K, mTOR or c-Met, suggesting that these receptors are amenable to inhibition using specific drug agents. In this review, we examine the mutational landscape of gastric cancer, the use of kinase inhibitors as targeted therapies in gastric tumours and the clinical trials underway for novel inhibitors, highlighting successes, failures and future directions.
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Affiliation(s)
- Batoul Farran
- Department of Structural and Molecular Biology, University College London, London, UK
| | - Susanne Müller
- Buchmann Institute for Molecular Life Sciences, Johann Wolfgang Goethe-University, Frankfurt am Main, DE, Germany
| | - Raquel C Montenegro
- Drug Research and Development Center, Federal University of Ceará, Fortaleza, CE, Brazil
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Mihailidou C, Karamouzis MV, Schizas D, Papavassiliou AG. Co-targeting c-Met and DNA double-strand breaks (DSBs): Therapeutic strategies in BRCA-mutated gastric carcinomas. Biochimie 2017; 142:135-143. [DOI: 10.1016/j.biochi.2017.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 09/04/2017] [Indexed: 02/06/2023]
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