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Abdoli Shadbad M, Baghbanzadeh A, Baradaran B. hsa-miR-34a-5p enhances temozolomide anti-tumoral effects on glioblastoma: in-silico and in-vitro study. EXCLI JOURNAL 2024; 23:384-400. [PMID: 38655096 PMCID: PMC11036064 DOI: 10.17179/excli2023-6404] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Accepted: 03/04/2024] [Indexed: 04/26/2024]
Abstract
Glioblastoma multiform (GBM) is a commonly diagnosed brain neoplasm with a poor prognosis. Accumulating evidence has highlighted the significance of microRNA (miR) dysregulation in tumor development and progression. This study investigated the effect of hsa-miR-34a-5p and its combination with temozolomide on GBM, the related molecular mechanisms, and the signaling pathway using in-silico and in-vitro approaches. The in-silico tumor bulk and single-cell RNA sequencing analyses were done on TCGA-GTEx, CGGA, GSE13276, GSE90603, and GSE182109 datasets. After selecting the A172 cell line, hsa-miR-34a-5p mimics were transfected, and the cell viability, migration, cell cycle, clonogenicity, and apoptosis of studied groups were studied using MTT, scratch, flow cytometry, colony formation, and Annexin V/PI assays. The mRNA expression of CASP9, CASP3, CASP8, MMP2, CD44, CDK6, CDK4, CCND1, RAF1, MAP2K1, MET, SRC, and CD274 was studied using qRT-PCR method. hsa-miR-34a-5p downregulated RAF1 expression, as the signaling factor of the MAPK pathway. The combined treatment significantly downregulated the expression of MET, SRC, and MAP2K1, leading to the inhibition of the MET/MAPK pathway compared to temozolomide. Besides exerting anti-tumoral effects on the cell viability, migration, cell cycle, apoptosis, and clonogenicity of A172 cells, its combination with temozolomide enhanced temozolomide anti-tumoral effect. Compared to temozolomide, the combined treatment significantly decreased CDK4, CDK6, CCND1, and MMP2 expression. hsa-miR-34a-5p targets RAF1, as the signaling factor of the MAPK pathway, and potentiates the temozolomide anti-tumoral effect on A172 cells.
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Affiliation(s)
- Mahdi Abdoli Shadbad
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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Al-Ghabkari A, Huang B, Park M. Aberrant MET Receptor Tyrosine Kinase Signaling in Glioblastoma: Targeted Therapy and Future Directions. Cells 2024; 13:218. [PMID: 38334610 PMCID: PMC10854665 DOI: 10.3390/cells13030218] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 11/27/2023] [Accepted: 01/12/2024] [Indexed: 02/10/2024] Open
Abstract
Brain tumors represent a heterogeneous group of neoplasms characterized by a high degree of aggressiveness and a poor prognosis. Despite recent therapeutic advances, the treatment of brain tumors, including glioblastoma (GBM), an aggressive primary brain tumor associated with poor prognosis and resistance to therapy, remains a significant challenge. Receptor tyrosine kinases (RTKs) are critical during development and in adulthood. Dysregulation of RTKs through activating mutations and gene amplification contributes to many human cancers and provides attractive therapeutic targets for treatment. Under physiological conditions, the Met RTK, the hepatocyte growth factor/scatter factor (HGF/SF) receptor, promotes fundamental signaling cascades that modulate epithelial-to-mesenchymal transition (EMT) involved in tissue repair and embryogenesis. In cancer, increased Met activity promotes tumor growth and metastasis by providing signals for proliferation, survival, and migration/invasion. Recent clinical genomic studies have unveiled multiple mechanisms by which MET is genetically altered in GBM, including focal amplification, chromosomal rearrangements generating gene fusions, and a splicing variant mutation (exon 14 skipping, METex14del). Notably, MET overexpression contributes to chemotherapy resistance in GBM by promoting the survival of cancer stem-like cells. This is linked to distinctive Met-induced pathways, such as the upregulation of DNA repair mechanisms, which can protect tumor cells from the cytotoxic effects of chemotherapy. The development of MET-targeted therapies represents a major step forward in the treatment of brain tumours. Preclinical studies have shown that MET-targeted therapies (monoclonal antibodies or small molecule inhibitors) can suppress growth and invasion, enhancing the efficacy of conventional therapies. Early-phase clinical trials have demonstrated promising results with MET-targeted therapies in improving overall survival for patients with recurrent GBM. However, challenges remain, including the need for patient stratification, the optimization of treatment regimens, and the identification of mechanisms of resistance. This review aims to highlight the current understanding of mechanisms underlying MET dysregulation in GBM. In addition, it will focus on the ongoing preclinical and clinical assessment of therapies targeting MET dysregulation in GBM.
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Affiliation(s)
- Abdulhameed Al-Ghabkari
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; (A.A.-G.); (B.H.)
| | - Bruce Huang
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; (A.A.-G.); (B.H.)
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
| | - Morag Park
- Rosalind and Morris Goodman Cancer Institute, McGill University, Montreal, QC H3A 1A3, Canada; (A.A.-G.); (B.H.)
- Department of Biochemistry, McGill University, Montreal, QC H3G 1Y6, Canada
- Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada
- Department of Medicine, McGill University, Montreal, QC H4A 3J1, Canada
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Yang X, Liao HY, Zhang HH. Roles of MET in human cancer. Clin Chim Acta 2021; 525:69-83. [PMID: 34951962 DOI: 10.1016/j.cca.2021.12.017] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 12/15/2021] [Accepted: 12/17/2021] [Indexed: 01/18/2023]
Abstract
The MET proto-oncogene was first identified in osteosarcoma cells exposed to carcinogens. Although expressed in many normal cells, MET is overexpressed in many human cancers. MET is involved in the initiation and development of various human cancers and mediates proliferation, migration and invasion. Accordingly, MET has been successfully used as a biomarker for diagnosis and prognosis, survival, post-operative recurrence, risk assessment and pathologic grading, as well as a therapeutic target. In addition, recent work indicates that inhibition of MET expression and function has potential clinical benefit. This review summarizes the role, mechanism, and clinical significance of MET in the formation and development of human cancer.
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Affiliation(s)
- Xin Yang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, PR China; Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou 730000, PR China
| | - Hai-Yang Liao
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, PR China; Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou 730000, PR China
| | - Hai-Hong Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou 730000, PR China; Department of Orthopaedics, Lanzhou University Second Hospital, Lanzhou 730000, PR China.
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HGF/MET Signaling in Malignant Brain Tumors. Int J Mol Sci 2020; 21:ijms21207546. [PMID: 33066121 PMCID: PMC7590206 DOI: 10.3390/ijms21207546] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/08/2020] [Accepted: 10/11/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocyte growth factor (HGF) ligand and its receptor tyrosine kinase (RTK) mesenchymal-epithelial transition factor (MET) are important regulators of cellular processes such as proliferation, motility, angiogenesis, and tissue regeneration. In healthy adult somatic cells, this ligand and receptor pair is expressed at low levels and has little activity except when tissue injuries arise. In cancer cells, HGF/MET are often overexpressed, and this overexpression is found to correlate with tumorigenesis, metastasis, and poorer overall prognosis. This review focuses on the signaling of these molecules in the context of malignant brain tumors. RTK signaling pathways are among the most common and universally dysregulated pathways in gliomas. We focus on the role of HGF/MET in the following primary malignant brain tumors: astrocytomas, glioblastomas, oligodendrogliomas, ependymomas, and embryonal central nervous system tumors (including medulloblastomas and others). Brain metastasis, as well as current advances in targeted therapies, are also discussed.
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Design, synthesis and biological evaluation of novel N-sulfonylamidine-based derivatives as c-Met inhibitors via Cu-catalyzed three-component reaction. Eur J Med Chem 2020; 200:112470. [PMID: 32505087 DOI: 10.1016/j.ejmech.2020.112470] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 05/09/2020] [Accepted: 05/13/2020] [Indexed: 12/28/2022]
Abstract
In our continuing efforts to develop novel c-Met inhibitors as potential anticancer candidates, a series of new N-sulfonylamidine derivatives were designed, synthesized via Cu-catalyzed multicomponent reaction (MCR) as the key step, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (A549, HT-29, MKN-45 and MDA-MB-231). Most of the target compounds showed moderate to significant potency at both the enzyme-based and cell-based assay and possessed selectivity for A549 and HT-29 cancer cell lines. The preliminary SAR studies demonstrated that compound 26af (c-Met IC50 = 2.89 nM) was the most promising compound compared with the positive foretinib, which exhibited the remarkable antiproliferative activities, with IC50 values ranging from 0.28 to 0.72 μM. Mechanistic studies of 26af showed the anticancer activity was closely related to the blocking phosphorylation of c-Met, leading to cell cycle arresting at G2/M phase and apoptosis of A549 cells by a concentration-dependent manner. The promising compound 26af was further identified as a relatively selective inhibitor of c-Met kinase, which also possessed an acceptable safety profile and favorable pharmacokinetic properties in BALB/c mouse. The favorable drug-likeness of 26af suggested that N-sulfonylamidines may be used as a promising scaffold for antitumor drug development. Additionally, the docking study and molecular dynamics simulations of 26af revealed a common mode of interaction with the binding site of c-Met. These positive results indicated that compound 26af is a potential anti-cancer candidate for clinical trials, and deserves further development as a selective c-Met inhibitor.
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Sun Z, Cai S, Zabkiewicz C, Liu C, Ye L. Bone morphogenetic proteins mediate crosstalk between cancer cells and the tumour microenvironment at primary tumours and metastases (Review). Int J Oncol 2020; 56:1335-1351. [PMID: 32236571 DOI: 10.3892/ijo.2020.5030] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 02/28/2020] [Indexed: 11/05/2022] Open
Abstract
Bone morphogenetic proteins (BMP) are pluripotent molecules, co‑ordinating cellular functions from early embryonic and postnatal development to tissue repair, regeneration and homeostasis. They are also involved in tumourigenesis, disease progression and the metastasis of various solid tumours. Emerging evidence has indicated that BMPs are able to promote disease progression and metastasis by orchestrating communication between cancer cells and the surrounding microenvironment. The interactions occur between BMPs and epidermal growth factor receptor, hepatocyte growth factor, fibroblast growth factor, vascular endothelial growth factor and extracellular matrix components. Overall, these interactions co‑ordinate the cellular functions of tumour cells and other types of cell in the tumour to promote the growth of the primary tumour, local invasion, angiogenesis and metastasis, and the establishment and survival of cancer cells in the metastatic niche. Therefore, the present study aimed to provide an informative summary of the involvement of BMPs in the tumour microenvironment.
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Affiliation(s)
- Zhiwei Sun
- VIP‑II Division of Medical Department, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education, Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, P.R. China
| | - Shuo Cai
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
| | - Catherine Zabkiewicz
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
| | - Chang Liu
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
| | - Lin Ye
- Cardiff China Medical Research Collaborative, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff CF14 4XN, United Kingdom
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Resveratrol Suppresses Prostate Cancer Epithelial Cell Scatter/Invasion by Targeting Inhibition of Hepatocyte Growth Factor (HGF) Secretion by Prostate Stromal Cells and Upregulation of E-cadherin by Prostate Cancer Epithelial Cells. Int J Mol Sci 2020; 21:ijms21051760. [PMID: 32143478 PMCID: PMC7084722 DOI: 10.3390/ijms21051760] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 01/23/2020] [Accepted: 03/02/2020] [Indexed: 12/17/2022] Open
Abstract
Cancer mortality is primarily attributed to metastasis and the resulting compromise of organs secondary to the initial tumor site. Metastasis is a multi-step process in which the tumor cells must first acquire a migratory phenotype and invade through the surrounding tissue for spread to distant organs in the body. The ability of malignant cells to migrate and breach surrounding tissue/matrix barriers is among the most daunting challenges to disease management for men in the United States diagnosed with prostate cancer (CaP), especially since, at diagnosis, a high proportion of patients already have occult or clinically-detectable metastasis. The interaction between hepatocyte growth factor (HGF) secreted by the stroma, with its receptor c-Met located in the epithelium, must occur for epithelial CaP cells to become migratory. We studied the effects of grape-derived phytochemical resveratrol on the transition of epithelial tumor cells from sedentary to a mobile, penetrant phenotype. A time lapse microscopy assay was used to monitor the acquisition of the migratory phenotype by resveratrol. The results show that resveratrol inhibits HGF-mediated interaction between the stroma and epithelium and suppresses epithelial CaP cell migration by attenuating the control of epithelial-to-mesenchymal transition (EMT).
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Xu Q, Hu C, Zhu Y, Wang K, Lal B, Li L, Tang J, Wei S, Huang G, Xia S, Lv S, Laterra J, Jiang Y, Li Y. ShRNA-based POLD2 expression knockdown sensitizes glioblastoma to DNA-Damaging therapeutics. Cancer Lett 2020; 482:126-135. [PMID: 31954770 DOI: 10.1016/j.canlet.2020.01.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2019] [Revised: 01/08/2020] [Accepted: 01/13/2020] [Indexed: 10/25/2022]
Abstract
Glioblastoma (GBM) has limited therapeutic options. DNA repair mechanisms contribute GBM cells to escape therapies and re-establish tumor growth. Multiple studies have shown that POLD2 plays a critical role in DNA replication, DNA repair and genomic stability. We demonstrate for the first time that POLD2 is highly expressed in human glioma specimens and that expression correlates with poor patient survival. siRNA or shRNA POLD2 inhibited GBM cell proliferation, cell cycle progression, invasiveness, sensitized GBM cells to chemo/radiation-induced cell death and reversed the cytoprotective effects of EGFR signaling. Conversely, forced POLD2 expression was found to induce GBM cell proliferation, colony formation, invasiveness and chemo/radiation resistance. POLD2 expression associated with stem-like cell subsets (CD133+ and SSEA-1+ cells) and positively correlated with Sox2 expression in clinical specimens. Its expression was induced by Sox2 and inhibited by the forced differentiation of GBM neurospheres. shRNA-POLD2 modestly inhibited GBM neurosphere-derived orthotopic xenografts growth, when combined with radiation, dramatically inhibited xenograft growth in a cooperative fashion. These novel findings identify POLD2 as a new potential therapeutic target for enhancing GBM response to current standard of care therapeutics.
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Affiliation(s)
- Qingfu Xu
- Department of Neurosurgery, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, PR China; Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, PR China; Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA
| | - Chengchen Hu
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA
| | - Yan Zhu
- Department of Ultrasonography, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, 510623, PR China; Department of Obstetrics and Gynecology, Xinqiao Hospital, Third Military Medical University, Chongqing, 400037, PR China
| | - Kimberly Wang
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA
| | - Bachuchu Lal
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA
| | - Lichao Li
- Department of Neurosurgery, The First Hospital of Lanzhou University, Lanzhou, Gansu, 730000, PR China
| | - Junhai Tang
- Department of Neurosurgery, Third Military Medical University, Chongqing, 400037, PR China
| | - Shuang Wei
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA
| | - Guohao Huang
- Department of Neurosurgery, Third Military Medical University, Chongqing, 400037, PR China
| | - Shuli Xia
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA
| | - Shengqing Lv
- Department of Neurosurgery, Third Military Medical University, Chongqing, 400037, PR China
| | - John Laterra
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA; Department of Oncology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA; Department of Neuroscience, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA
| | - Yugang Jiang
- Department of Neurosurgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, 410011, PR China
| | - Yunqing Li
- Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, 21205, USA; Department of Neurology, The Johns Hopkins University School of Medicine, 600 N. Wolfe Street, Baltimore, MD, 21287, USA.
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SPINT2 is hypermethylated in both IDH1 mutated and wild-type glioblastomas, and exerts tumor suppression via reduction of c-Met activation. J Neurooncol 2019; 142:423-434. [PMID: 30838489 DOI: 10.1007/s11060-019-03126-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2018] [Accepted: 02/09/2019] [Indexed: 02/07/2023]
Abstract
PURPOSE Both IDH1-mutated and wild-type gliomas abundantly display aberrant CpG island hypermethylation. However, the potential role of hypermethylation in promoting gliomas, especially the most aggressive form, glioblastoma (GBM), remains poorly understood. METHODS We analyzed RRBS-generated methylation profiles for 11 IDH1WT gliomas (including 7 GBMs), 24 IDH1MUT gliomas (including 6 GBMs), and 5 normal brain samples and employed TCGA GBM methylation profiles as a validation set. Upon classification of differentially methylated CpG islands by IDH1 status, we used integrated analysis of methylation and gene expression to identify SPINT2 as a top cancer related gene. To explore functional consequences of SPINT2 methylation in GBM, we validated SPINT2 methylation status using targeted bisulfite sequencing in a large cohort of GBM samples. We assessed DNA methylation-mediated SPINT2 gene regulation using 5-aza-2'-deoxycytidine treatment, DNMT1 knockdown and luciferase reporter assays. We conducted functional analyses of SPINT2 in GBM cell lines in vitro and in vivo. RESULTS We identified SPINT2 as a candidate tumor-suppressor gene within a group of CpG islands (designated GT-CMG) that are hypermethylated in both IDH1MUT and IDH1WT gliomas but not in normal brain. We established that SPINT2 downregulation results from promoter hypermethylation, and that restoration of SPINT2 expression reduces c-Met activation and tumorigenic properties of GBM cells. CONCLUSIONS We defined a previously under-recognized group of coordinately methylated CpG islands common to both IDH1WT and IDH1MUT gliomas (GT-CMG). Within GT-CMG, we identified SPINT2 as a top cancer-related candidate and demonstrated that SPINT2 suppressed GBM via down-regulation of c-Met activation.
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Rashed WM. C-MET as a potential target therapy toward personalized therapy in some pediatric tumors: An overview. Crit Rev Oncol Hematol 2018; 131:7-15. [DOI: 10.1016/j.critrevonc.2018.08.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 08/22/2018] [Indexed: 12/28/2022] Open
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Cruickshanks N, Zhang Y, Hine S, Gibert M, Yuan F, Oxford M, Grello C, Pahuski M, Dube C, Guessous F, Wang B, Deveau C, Saoud K, Gallagher I, Wulfkuhle J, Schiff D, Phan S, Petricoin E, Abounader R. Discovery and Therapeutic Exploitation of Mechanisms of Resistance to MET Inhibitors in Glioblastoma. Clin Cancer Res 2018; 25:663-673. [PMID: 30201763 DOI: 10.1158/1078-0432.ccr-18-0926] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 06/13/2018] [Accepted: 09/05/2018] [Indexed: 12/14/2022]
Abstract
PURPOSE Glioblastoma (GBM) is the most common and most lethal primary malignant brain tumor. The receptor tyrosine kinase MET is frequently upregulated or overactivated in GBM. Although clinically applicable MET inhibitors have been developed, resistance to single modality anti-MET drugs frequently occurs, rendering these agents ineffective. We aimed to determine the mechanisms of MET inhibitor resistance in GBM and use the acquired information to develop novel therapeutic approaches to overcome resistance.Experimental Design: We investigated two clinically applicable MET inhibitors: crizotinib, an ATP-competitive small molecule inhibitor of MET, and onartuzumab, a monovalent monoclonal antibody that binds to the extracellular domain of the MET receptor. We developed new MET inhibitor-resistant cells lines and animal models and used reverse phase protein arrays (RPPA) and functional assays to uncover the compensatory pathways in MET inhibitor-resistant GBM. RESULTS We identified critical proteins that were altered in MET inhibitor-resistant GBM including mTOR, FGFR1, EGFR, STAT3, and COX-2. Simultaneous inhibition of MET and one of these upregulated proteins led to increased cell death and inhibition of cell proliferation in resistant cells compared with either agent alone. In addition, in vivo treatment of mice bearing MET-resistant orthotopic xenografts with COX-2 or FGFR pharmacological inhibitors in combination with MET inhibitor restored sensitivity to MET inhibition and significantly inhibited tumor growth. CONCLUSIONS These data uncover the molecular basis of adaptive resistance to MET inhibitors and identify new FDA-approved multidrug therapeutic combinations that can overcome resistance.
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Affiliation(s)
- Nichola Cruickshanks
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Ying Zhang
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Sarah Hine
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Myron Gibert
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Fang Yuan
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Madison Oxford
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Cassandra Grello
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Mary Pahuski
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Collin Dube
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Fadila Guessous
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia.,University Mohammed 6 for Health Sciences, Casablanca, Morocco
| | - Baomin Wang
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Ciana Deveau
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Karim Saoud
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia
| | - Isela Gallagher
- George Mason University Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia
| | - Julia Wulfkuhle
- George Mason University Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia
| | - David Schiff
- Department of Neurology, University of Virginia, Charlottesville, Virginia
| | - See Phan
- Genentech Inc. South San Francisco, California
| | - Emanuel Petricoin
- George Mason University Center for Applied Proteomics and Molecular Medicine, Manassas, Virginia
| | - Roger Abounader
- Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, Virginia. .,Department of Neurology, University of Virginia, Charlottesville, Virginia.,The Cancer Center, University of Virginia, Charlottesville, Virginia
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Xia GS, Li SH, Zhou W. Isoquercitrin, ingredients in Tetrastigma hemsleyanum Diels et Gilg, inhibits hepatocyte growth factor/scatter factor-induced tumor cell migration and invasion. Cell Adh Migr 2018; 12:464-471. [PMID: 29741444 DOI: 10.1080/19336918.2018.1473664] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aberrant activation of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, is involved in the development and progression of many human cancers. In the screening assay of extracts from the root tuber of Tetrastigma hemsleyanum Diels et Gilg, isoquercitrin inhibited HGF/SF-Met signaling as indicated by its inhibitory activity on HGF/SF-induced cell scattering. Further analysis revealed that isoquercitrin specifically inhibited HGF/SF-induced tyrosine phosphorylation of Met. We also found that isoquercitrin decreased HGF-induced migration and invasion by parental or HGF/SF-transfected bladder carcinoma cell line NBT-II cells. Furthermore, isoquercitrin inhibited HGF/SF-induced epithelial mesenchymal transition in vitro and the invasion/metastasis of HGF/SF-transfected NBT-II cells in vivo. Our data suggest the possible use of isoquercitrin in human cancers associated with dysregulated HGF/SF-Met signaling.
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Affiliation(s)
- Geng-Shou Xia
- a Department of Ecology , Lishui University , Lishui , Zhejiang , China
| | - Shu-Hong Li
- b Department of Medicine and Health , Lishui University , Lishui , Zhejiang , China
| | - Wu Zhou
- b Department of Medicine and Health , Lishui University , Lishui , Zhejiang , China
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13
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The multiple paths towards MET receptor addiction in cancer. Oncogene 2018; 37:3200-3215. [PMID: 29551767 DOI: 10.1038/s41388-018-0185-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 01/30/2018] [Accepted: 01/30/2018] [Indexed: 12/14/2022]
Abstract
Targeted therapies against receptor tyrosine kinases (RTKs) are currently used with success on a small proportion of patients displaying clear oncogene activation. Lung cancers with a mutated EGFR provide a good illustration. The efficacy of targeted treatments relies on oncogene addiction, a situation in which the growth or survival of the cancer cells depends on a single deregulated oncogene. MET, a member of the RTK family, is a promising target because it displays many deregulations in a broad panel of cancers. Although clinical trials having evaluated MET inhibitors in large populations have yielded disappointing results, many recent case reports suggest that MET inhibition may be effective in a subset of patients with unambiguous MET activation and thus, most probably, oncogene addiction. Interestingly, preclinical studies have revealed a particularity of MET addiction: it can arise through several mechanisms, and the mechanism involved can differ according to the cancer type. The present review describes the different mechanisms of MET addiction and their consequences for diagnosis and therapeutic strategies. Although in each cancer type MET addiction affects a restricted number of patients, pooling of these patients across all cancer types yields a targetable population liable to benefit from addiction-targeting therapies.
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14
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Huang D, Huang L, Zhang Q, Li J. Synthesis and biological evaluation of novel 6,11-dihydro-5 H -benzo[e]pyrimido- [5,4- b ][1,4]diazepine derivatives as potential c-Met inhibitors. Eur J Med Chem 2017; 140:212-228. [DOI: 10.1016/j.ejmech.2017.08.060] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Revised: 08/26/2017] [Accepted: 08/28/2017] [Indexed: 02/08/2023]
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15
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Clémenson C, Chargari C, Liu W, Mondini M, Ferté C, Burbridge MF, Cattan V, Jacquet-Bescond A, Deutsch E. The MET/AXL/FGFR Inhibitor S49076 Impairs Aurora B Activity and Improves the Antitumor Efficacy of Radiotherapy. Mol Cancer Ther 2017; 16:2107-2119. [PMID: 28619752 DOI: 10.1158/1535-7163.mct-17-0112] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 04/21/2017] [Accepted: 06/05/2017] [Indexed: 11/16/2022]
Abstract
Several therapeutic agents targeting HGF/MET signaling are under clinical development as single agents or in combination, notably with anti-EGFR therapies in non-small cell lung cancer (NSCLC). However, despite increasing data supporting a link between MET, irradiation, and cancer progression, no data regarding the combination of MET-targeting agents and radiotherapy are available from the clinic. S49076 is an oral ATP-competitive inhibitor of MET, AXL, and FGFR1-3 receptors that is currently in phase I/II clinical trials in combination with gefitinib in NSCLC patients whose tumors show resistance to EGFR inhibitors. Here, we studied the impact of S49076 on MET signaling, cell proliferation, and clonogenic survival in MET-dependent (GTL16 and U87-MG) and MET-independent (H441, H460, and A549) cells. Our data show that S49076 exerts its cytotoxic activity at low doses on MET-dependent cells through MET inhibition, whereas it inhibits growth of MET-independent cells at higher but clinically relevant doses by targeting Aurora B. Furthermore, we found that S49076 improves the antitumor efficacy of radiotherapy in both MET-dependent and MET-independent cell lines in vitro and in subcutaneous and orthotopic tumor models in vivo In conclusion, our study demonstrates that S49076 has dual antitumor activity and can be used in combination with radiotherapy for the treatment of both MET-dependent and MET-independent tumors. These results support the evaluation of combined treatment of S49076 with radiation in clinical trials without patient selection based on the tumor MET dependency status. Mol Cancer Ther; 16(10); 2107-19. ©2017 AACR.
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Affiliation(s)
- Céline Clémenson
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France
| | - Cyrus Chargari
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.,Gustave Roussy, Université Paris-Saclay, Département de Radiothérapie, Villejuif, France.,Institut de Recherche Biomédicale des Armées, Brétigny-Sur-Orge, France
| | - Winchygn Liu
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France
| | - Michele Mondini
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France
| | - Charles Ferté
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France.,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.,INSERM, U981, Villejuif, France
| | - Mike F Burbridge
- Oncology Unit, Institut de Recherches Internationales Servier, Suresnes, France
| | - Valérie Cattan
- Oncology Unit, Institut de Recherches Internationales Servier, Suresnes, France
| | | | - Eric Deutsch
- Gustave Roussy, Université Paris-Saclay, UMR Radiothérapie Moléculaire, Villejuif, France. .,INSERM, U1030, SIRIC Socrates, DHU TORINO, Villejuif, France.,Gustave Roussy, Université Paris-Saclay, Département de Radiothérapie, Villejuif, France.,Univ Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France
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16
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Effect of brefelamide on HGF-induced survival of 1321N1 human astrocytoma cells. In Vitro Cell Dev Biol Anim 2016; 52:705-11. [PMID: 27130674 DOI: 10.1007/s11626-016-0019-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/17/2016] [Indexed: 10/21/2022]
Abstract
Malignant gliomas are characterized by their high level of resistance to chemo- and radiotherapy and new treatment options are urgently required. We previously demonstrated that brefelamide, an aromatic amide isolated from methanol extracts of cellular slime molds Dictyostelium brefeldianum and D. giganteum, had antiproliferative effects on 1321N1 human astrocytoma cells, a model of glioma. In this study, we investigated the mechanisms by which brefelamide inhibited 1321N1 and PC12 rat pheochromocytoma cell proliferation. When cells were cultured in serum-free medium, hepatocyte growth factor (HGF) increased survival of 1321N1 cells but not PC12 cells. HGF receptor, c-MET, was strongly expressed in 1321N1 cells, but not in PC12 cells. Pretreatment of 1321N1 cells with brefelamide inhibited both HGF-induced cell survival and expression of c-MET. Phosphorylation of extracellular signal-regulated kinase (ERK) and AKT was increased by HGF, but these changes were inhibited by brefelamide pretreatment. Moreover, HGF mRNA levels and secretion were reduced by brefelamide. These results suggest that brefelamide reduces survival of 1321N1 cells via multiple effects including suppression of HGF receptor expression and HGF secretion and inhibition of ERK and AKT phosphorylation.
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Abstract
Glioblastoma multiforme is the most common and most lethal of all primary brain tumors. Even with the standard therapy, life expectancy is still poor, with an average survival of approximately 14 months following initial diagnosis. Hence, there is an urgent need for novel treatment strategies that inhibit proliferation and angiogenesis in high-grade gliomas. One such strategy consists of inhibiting receptor tyrosine kinases, including MET and/or its ligand hepatocyte growth factor (HGF). Because of their widespread involvement in human cancer, HGF and MET have emerged as promising therapeutic targets, and some inhibitory agents that target them have already entered clinical trials. In this paper, the authors highlight recent evidence implicating HGF/MET pathway deregulation in glioblastoma multiforme, discuss therapeutic approaches to inhibit HGF/MET signaling, and summarize ongoing clinical trials targeting this pathway.
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Womeldorff M, Gillespie D, Jensen RL. Hypoxia-inducible factor-1 and associated upstream and downstream proteins in the pathophysiology and management of glioblastoma. Neurosurg Focus 2015; 37:E8. [PMID: 25581937 DOI: 10.3171/2014.9.focus14496] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an exceptionally poor patient outcome despite aggressive therapy including surgery, radiation, and chemotherapy. This aggressive phenotype may be associated with intratumoral hypoxia, which probably plays a key role in GBM tumor growth, development, and angiogenesis. A key regulator of cellular response to hypoxia is the protein hypoxia-inducible factor–1 (HIF-1). An examination of upstream hypoxic and nonhypoxic regulation of HIF-1 as well as a review of the downstream HIF-1– regulated proteins may provide further insight into the role of this transcription factor in GBM pathophysiology. Recent insights into upstream regulators that intimately interact with HIF-1 could provide potential therapeutic targets for treatment of this tumor. The same is potentially true for HIF-1–mediated pathways of glycolysis-, angiogenesis-, and invasion-promoting proteins. Thus, an understanding of the relationship between HIF-1, its upstream protein regulators, and its downstream transcribed genes in GBM pathogenesis could provide future treatment options for the care of patients with these tumors.
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Chen HM, Yu K, Tang XY, Bao ZS, Jiang T, Fan XL, Chen XW, Su XD. Enhanced expression and phosphorylation of the MET oncoprotein by glioma-specific PTPRZ1-MET fusions. FEBS Lett 2015; 589:1437-43. [PMID: 25935522 DOI: 10.1016/j.febslet.2015.04.032] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2015] [Revised: 03/30/2015] [Accepted: 04/15/2015] [Indexed: 11/27/2022]
Abstract
PTPRZ1-MET (ZM) proteins are a group of fusion proteins identified in human gliomas by high-throughput transcriptome sequencing. ZM fusions are associated with poor prognosis in afflicted glioma patients and mediate oncogenic effects in assays. In this study, we show that ZM-carrying patients have increased hepatocyte growth factor receptor (MET) mRNA expression levels induced by fusion with receptor-type tyrosine-protein phosphatase zeta (PTPRZ1). Furthermore, ZM fusions preserve fundamental properties of wild-type MET with respect to processing and dimerization, and enhance phosphorylation in an hepatocyte growth factor (HGF)-dependent and independent manner. Our findings suggest that ZM induces gliomas through elevated expression and phosphorylation of the MET oncoprotein.
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Affiliation(s)
- Hui-Min Chen
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China; School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Kai Yu
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China
| | - Xiao-yan Tang
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China
| | - Zhao-shi Bao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Beijing Neurosurgical Institute, Beijing 100050, China
| | - Tao Jiang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing 100050, China; Beijing Neurosurgical Institute, Beijing 100050, China
| | - Xiao-Long Fan
- Laboratory of Neuroscience and Brain Development, Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing Normal University, Beijing, China
| | - Xiao-Wei Chen
- Institute of Molecular Medicine, Centre for Life Sciences, Peking University, Beijing 100871, China
| | - Xiao-Dong Su
- Biodynamic Optical Imaging Center (BIOPIC), School of Life Sciences, Peking University, Beijing 100871, China.
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20
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Radiation therapy for glioma stem cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2015; 853:85-110. [PMID: 25895709 DOI: 10.1007/978-3-319-16537-0_6] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Radiation therapy is the most effective adjuvant treatment modality for virtually all patients with high-grade glioma. Its ability to improve patient survival has been recognized for decades. Cancer stem cells provide new insights into how tumor biology is affected by radiation and the role that this cell population can play in disease recurrence. Glioma stem cells possess a variety of intracellular mechanisms to resist and even flourish in spite of radiation, and their proliferation and maintenance appear tied to supportive stimuli from the tumor microenvironment. This chapter reviews the basis for our current use of radiation to treat high-grade gliomas, and addresses this model in the context of therapeutically resistant stem cells. We discuss the available evidence highlighting current clinical efforts to improve radiosensitivity, and newer targets worthy of further development.
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21
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Zhou S, Liao H, Liu M, Feng G, Fu B, Li R, Cheng M, Zhao Y, Gong P. Discovery andw biological evaluation of novel 6,7-disubstituted-4-(2-fluorophenoxy)quinoline derivatives possessing 1,2,3-triazole-4-carboxamide moiety as c-Met kinase inhibitors. Bioorg Med Chem 2014; 22:6438-52. [DOI: 10.1016/j.bmc.2014.09.037] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 09/16/2014] [Accepted: 09/17/2014] [Indexed: 10/24/2022]
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22
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Zhang Y, Schiff D, Park D, Abounader R. MicroRNA-608 and microRNA-34a regulate chordoma malignancy by targeting EGFR, Bcl-xL and MET. PLoS One 2014; 9:e91546. [PMID: 24621885 PMCID: PMC3951453 DOI: 10.1371/journal.pone.0091546] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2013] [Accepted: 02/12/2014] [Indexed: 11/19/2022] Open
Abstract
Chordomas are rare malignant tumors that originate from the notochord remnants and occur in the skull base, spine and sacrum. Due to a very limited understanding of the molecular pathogenesis of chordoma, there are no adjuvant and molecular therapies besides surgical resection and radiation therapy. microRNAs (miRNAs) are small noncoding regulatory RNA molecules with critical roles in cancer. The role of miRNAs in chordomas is mostly unknown. We uncover microRNA-608 (miR-608) and microRNA-34a (miR-34a) as novel tumor suppressive microRNAs that regulate malignancy in chordoma. We find that miR-608 and miR-34a expressions are downregulated in human chordoma cell lines and primary cells at least partially via alteration of their genes' copy numbers. We identify the commonly deregulated oncogenes EGFR and Bcl-xL as direct targets of miR-608 and the receptor tyrosine kinase MET as direct target of miR-34a. We show that EGFR and MET activations promote chordoma cell proliferation and invasion and that pharmacological inhibition of EGFR and MET inhibits chordoma cell proliferation and survival. We demonstrate that restoration of miR-608 and miR-34a inhibits cell proliferation and invasion and induces apoptosis in chordoma cells. We find that miR-34a inversely correlates with MET expression and miR-608 inversely correlates with EGFR expression in chordoma cells. These findings demonstrate for the first time that miR-608 and miR-34a regulate chordoma malignancy by regulating EGFR, MET and Bcl-xL.
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Affiliation(s)
- Ying Zhang
- Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail: (YZ); (RA)
| | - David Schiff
- Department of Neurology, University of Virginia, Charlottesville, Virginia, United States of America
| | - Deric Park
- Department of Neurosurgery, University of Virginia, Charlottesville, Virginia, United States of America
| | - Roger Abounader
- Departments of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia, United States of America
- Department of Neurology, University of Virginia, Charlottesville, Virginia, United States of America
- Cancer Center, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail: (YZ); (RA)
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23
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Murray DW, Didier S, Chan A, Paulino V, Van Aelst L, Ruggieri R, Tran NL, Byrne AT, Symons M. Guanine nucleotide exchange factor Dock7 mediates HGF-induced glioblastoma cell invasion via Rac activation. Br J Cancer 2014; 110:1307-15. [PMID: 24518591 PMCID: PMC3950876 DOI: 10.1038/bjc.2014.39] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 11/11/2013] [Accepted: 01/07/2014] [Indexed: 02/08/2023] Open
Abstract
Background: Glioblastoma multiforme (GBM), a highly invasive primary brain tumour, remains an incurable disease. Rho GTPases and their activators, guanine nucleotide exchange factors (GEFs), have central roles in GBM invasion. Anti-angiogenic therapies may stimulate GBM invasion via HGF/c-Met signalling. We aim to identify mediators of HGF-induced GBM invasion that may represent targets in a combination anti-angiogenic/anti-invasion therapeutic paradigm. Methods: Guanine nucleotide exchange factor expression was measured by microarray analysis and western blotting. Specific depletion of proteins was accomplished using siRNA. Cell invasion was determined using matrigel and brain slice assays. Cell proliferation and survival were monitored using sulforhodamine B and colony formation assays. Guanine nucleotide exchange factor and GTPase activities were determined using specific affinity precipitation assays. Results: We found that expression of Dock7, a GEF, is elevated in human GBM tissue in comparison with non-neoplastic brain. We showed that Dock7 mediates serum- and HGF-induced glioblastoma cell invasion. We also showed that Dock7 co-immunoprecipitates with c-Met and that this interaction is enhanced upon HGF stimulation in a manner that is dependent on the adaptor protein Gab1. Dock7 and Gab1 also co-immunoprecipitate in an HGF-dependent manner. Furthermore, Gab1 is required for HGF-induced Dock7 and Rac1 activation and glioblastoma cell invasion. Conclusions: Dock7 mediates HGF-induced GBM invasion. Targeting Dock7 in GBM may inhibit c-MET-mediated invasion in tumours treated with anti-angiogenic regimens.
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Affiliation(s)
- D W Murray
- 1] Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens' Green, Dublin 2, Ireland [2] Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA
| | - S Didier
- Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA
| | - A Chan
- Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA
| | - V Paulino
- Cancer and Cell Biology Division, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ 85004, USA
| | - L Van Aelst
- Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, NY 11724, USA
| | - R Ruggieri
- Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA
| | - N L Tran
- Cancer and Cell Biology Division, Translational Genomics Research Institute, 445 N. Fifth Street, Phoenix, AZ 85004, USA
| | - A T Byrne
- 1] Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, 123 St. Stephens' Green, Dublin 2, Ireland [2] UCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin, Dublin 4, Ireland
| | - M Symons
- Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, 350 Community Drive, Manhasset, NY 11030, USA
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Regulation of HGF expression by ΔEGFR-mediated c-Met activation in glioblastoma cells. Neoplasia 2013; 15:73-84. [PMID: 23359207 DOI: 10.1593/neo.121536] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2012] [Revised: 11/28/2012] [Accepted: 11/29/2012] [Indexed: 11/18/2022]
Abstract
The hepatocyte growth factor receptor (c-Met) and a constitutively active mutant of the epidermal growth factor receptor (ΔEGFR/EGFRvIII) are frequently overexpressed in glioblastoma (GBM) and promote tumorigenesis. The mechanisms underlying elevated hepatocyte growth factor (HGF) production in GBM are not understood. We found higher, coordinated mRNA expression levels of HGF and c-Met in mesenchymal (Mes) GBMs, a subtype associated with poor treatment response and shorter overall survival. In an HGF/c-Met-dependent GBM cell line, HGF expression declined upon silencing of c-Met using RNAi or by inhibiting its activity with SU11274. Silencing c-Met decreased anchorage-independent colony formation and increased the survival of mice bearing intracranial GBM xenografts. Consistent with these findings, c-Met activation by ΔEGFR also elevated HGF expression, and the inhibition of ΔEGFR with AG1478 reduced HGF levels. Interestingly, c-Met expression was required for ΔEGFR-mediated HGF production, anchorage-independent growth, and in vivo tumorigenicity, suggesting that these pathways are coupled. Using an unbiased mass spectrometry-based screen, we show that signal transducer and activator of transcription 3 (STAT3) Y705 is a downstream target of c-Met signaling. Suppression of STAT3 phosphorylation with WP1193 reduced HGF expression in ΔEGFR-expressing GBM cells, whereas constitutively active STAT3 partially rescued HGF expression and colony formation in c-Met knockdown cells expressing ΔEGFR. These results suggest that the c-Met/HGF signaling axis is enhanced by ΔEGFR through increased STAT3-dependent HGF expression and that targeting c-Met in Mes GBMs may be an important strategy for therapy.
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Abstract
PURPOSE OF REVIEW The mesenchymal-epidermal transition (c-MET) receptor tyrosine kinase has a central role in the cancer cell's survival. MET and its ligand, hepatocyte growth factor (HGF), have recently been identified as promising targets in solid tumors, including nonsmall-cell lung cancer (NSCLC). RECENT FINDINGS Aberrant MET activation can be the result of different mechanisms such as MET and HGF overexpression, MET gene amplification or mutation. Retrospective studies in NSCLC showed that MET gene copy number is a negative prognostic factor, although few data are available on the role of MET mutations. In preclinical models, cell lines with MET gene amplification are extremely sensitive to MET inhibition. Although the inner presence of gene amplification is a rare event (1-7% cases), MET amplification has emerged as one of the critical events for acquired resistance in epidermal growth factor receptor (EGFR) mutated lung adenocarcinomas refractory to EGFR-tyrosine kinase inhibitors (TKIs). In NSCLC with acquired resistance to EGFR-TKIs, MET amplification occurs in up to 20% cases and preclinical and clinical data indicated MET and EGFR co-inhibition as a potential effective strategy to overcome resistance. SUMMARY MET has recently emerged as a promising target, and ongoing trials will clarify the role of anti-MET strategies in NSCLC.
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26
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Graveel CR, Tolbert D, Vande Woude GF. MET: a critical player in tumorigenesis and therapeutic target. Cold Spring Harb Perspect Biol 2013; 5:a009209. [PMID: 23818496 PMCID: PMC3685898 DOI: 10.1101/cshperspect.a009209] [Citation(s) in RCA: 97] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Since its discovery more than 25 years ago, numerous studies have established that the MET receptor is unique among tyrosine kinases. Signaling through MET is necessary for normal development and for the progression of a wide range of human cancers. MET activation has been shown to drive numerous signaling pathways; however, it is not clear how MET signaling mediates diverse cellular responses such as motility, invasion, growth, and angiogenesis. Great strides have been made in understanding the pleotropic aspects of MET signaling using three-dimensional molecular structures, cell culture systems, human tumors, and animal models. These combined approaches have driven the development of MET-targeted therapeutics that have shown promising results in the clinic. Here we examine the unique features of MET and hepatocyte growth factor/scatter factor (HGF/SF) structure and signaling, mutational activation, genetic mouse models of MET and HGF/SF, and MET-targeted therapeutics.
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Affiliation(s)
- Carrie R Graveel
- Molecular Oncology, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
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Discovery of novel 4-(2-fluorophenoxy)quinoline derivatives bearing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety as c-Met kinase inhibitors. Bioorg Med Chem 2013; 21:2843-55. [PMID: 23628470 DOI: 10.1016/j.bmc.2013.04.013] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 04/01/2013] [Accepted: 04/04/2013] [Indexed: 12/24/2022]
Abstract
A series of novel 4-(2-fluorophenoxy)quinoline derivatives containing 4-oxo-1,4-dihydrocinnoline-3-carboxamide moiety were designed, synthesized and evaluated for their in vitro biological activities against c-Met kinase and six typical cancer cell lines (A549, H460, HT-29, MKN-45, U87MG and SMMC-7721). All the prepared compounds showed moderate to excellent antiproliferative activity, and the analysis of their structure-activity relationships indicated that 2-chloro or 2-trifluoromethyl substituted phenyl group on the 1-position of cinnoline ring was more favorable for antitumor activity. In this study, a promising compound 33, with a c-Met IC50 value of 0.59 nM, was identified as a multitargeted receptor tyrosine kinase inhibitor.
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28
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Rivera M, Sukhdeo K, Yu J. Ionizing radiation in glioblastoma initiating cells. Front Oncol 2013; 3:74. [PMID: 23579692 PMCID: PMC3619126 DOI: 10.3389/fonc.2013.00074] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2012] [Accepted: 03/23/2013] [Indexed: 01/07/2023] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults with a median survival of 12-15 months with treatment consisting of surgical resection followed by ionizing radiation (IR) and chemotherapy. Even aggressive treatment is often palliative due to near universal recurrence. Therapeutic resistance has been linked to a subpopulation of GBM cells with stem cell-like properties termed GBM initiating cells (GICs). Recent efforts have focused on elucidating resistance mechanisms activated in GICs in response to IR. Among these, GICs preferentially activate the DNA damage response (DDR) to result in a faster rate of double-strand break (DSB) repair induced by IR as compared to the bulk tumor cells. IR also activates NOTCH and the hepatic growth factor (HGF) receptor, c-MET, signaling cascades that play critical roles in promoting proliferation, invasion, and resistance to apoptosis. These pathways are preferentially activated in GICs and represent targets for pharmacologic intervention. While IR provides the benefit of improved survival, it paradoxically promotes selection of more malignant cellular phenotypes of GBM. As reviewed here, finding effective combinations of radiation and molecular inhibitors to target GICs and non-GICs is essential for the development of more effective therapies.
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Affiliation(s)
- Maricruz Rivera
- Department of Stem Cell Biology and Regenerative Medicine, Lerner Research Institute, Cleveland Clinic Cleveland, OH, USA ; Department of Molecular Medicine, Lerner College of Medicine of Case Western Reserve University Cleveland Clinic, Cleveland, OH, USA
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29
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Zhang Y, Farenholtz KE, Yang Y, Guessous F, Dipierro CG, Calvert VS, Deng J, Schiff D, Xin W, Lee JK, Purow B, Christensen J, Petricoin E, Abounader R. Hepatocyte growth factor sensitizes brain tumors to c-MET kinase inhibition. Clin Cancer Res 2013; 19:1433-44. [PMID: 23386689 DOI: 10.1158/1078-0432.ccr-12-2832] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. EXPERIMENTAL DESIGN We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line-derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. RESULTS We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor. CONCLUSIONS These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors.
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Affiliation(s)
- Ying Zhang
- Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
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Mizuno S, Nakamura T. HGF-MET cascade, a key target for inhibiting cancer metastasis: the impact of NK4 discovery on cancer biology and therapeutics. Int J Mol Sci 2013; 14:888-919. [PMID: 23296269 PMCID: PMC3565297 DOI: 10.3390/ijms14010888] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Revised: 12/06/2012] [Accepted: 12/10/2012] [Indexed: 01/14/2023] Open
Abstract
Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, wild-type MET was shown to be a functional receptor of HGF. Indeed, HGF exerts multiple functions, such as proliferation, morphogenesis and anti-apoptosis, in various cells via MET tyrosine kinase phosphorylation. During the past 20 years, we have accumulated evidence that HGF is an essential conductor for embryogenesis and tissue regeneration in various types of organs. Furthermore, we found in the mid-1990s that stroma-derived HGF is a major contributor to cancer invasion at least in vitro. Based on this background, we prepared NK4 as an antagonist of HGF: NK4 inhibits HGF-mediated MET tyrosine phosphorylation by competing with HGF for binding to MET. In vivo, NK4 treatments produced the anti-tumor outcomes in mice bearing distinct types of malignant cancers, associated with the loss in MET activation. There are now numerous reports showing that HGF-antagonists and MET-inhibitors are logical for inhibiting tumor growth and metastasis. Additionally, NK4 exerts anti-angiogenic effects, partly through perlecan-dependent cascades. This paper focuses on the chronology and significance of HGF-antagonisms in anti-tumor researches, with an interest in NK4 discovery. Tumor HGF–MET axis is now critical for drug resistance and cancer stem cell maintenance. Thus, oncologists cannot ignore this cascade for the future success of anti-metastatic therapy.
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Affiliation(s)
- Shinya Mizuno
- Division of Virology, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, 2-2-B7 Yamadaoka, Suita 565-0871, Japan; E-Mail:
| | - Toshikazu Nakamura
- Division for Regenerative Drug Discovery, Center for Advanced Science and Innovation, Osaka University, 2-1 Yamadaoka, Suita 565-0871, Japan
- Author to whom correspondence should be addressed; E-Mail: ; Tel./Fax: +81-6-6879-4130
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Wang K, Zhuang Y, Liu C, Li Y. Inhibition of c-Met activation sensitizes osteosarcoma cells to cisplatin via suppression of the PI3K–Akt signaling. Arch Biochem Biophys 2012; 526:38-43. [DOI: 10.1016/j.abb.2012.07.003] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2012] [Revised: 07/05/2012] [Accepted: 07/06/2012] [Indexed: 11/27/2022]
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Michaud NR, Jani JP, Hillerman S, Tsaparikos KE, Barbacci-Tobin EG, Knauth E, Putz H, Campbell M, Karam GA, Chrunyk B, Gebhard DF, Green LL, Xu JJ, Dunn MC, Coskran TM, Lapointe JM, Cohen BD, Coleman KG, Bedian V, Vincent P, Kajiji S, Steyn SJ, Borzillo GV, Los G. Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621. MAbs 2012; 4:710-23. [PMID: 23007574 DOI: 10.4161/mabs.22160] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72-96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer.
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Affiliation(s)
- Neil R Michaud
- Pfizer Global Research and Development, Groton, CT, USA.
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The role of semaphorins and their receptors in gliomas. JOURNAL OF SIGNAL TRANSDUCTION 2012; 2012:902854. [PMID: 23050142 PMCID: PMC3461631 DOI: 10.1155/2012/902854] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/22/2012] [Accepted: 08/06/2012] [Indexed: 12/12/2022]
Abstract
Gliomas are the most common tumor in the central nervous system. High-grade glioblastomas are characterized by their high invasiveness and resistance to radiotherapy, leading to high recurrence rate and short median survival despite radical surgical resection. Characterizations of gliomas at molecular level have revealed aberrations of various growth factor receptors, receptor tyrosine kinases, and tumor suppressor genes that lead to deregulation of multiple signaling pathways, thereby contributing to abnormal proliferation, invasion, and resistance to apoptosis in cancer cells. Recently, accumulating evidence points to the emerging role of axon guidance molecules in glioma progression. Notably, many signaling events harnessed by guidance molecules to regulate cell migration and axon navigation during development are also found to be involved in the modulation of deregulated pathways in gliomas. This paper focused on the signalings triggered by the guidance molecule semaphorins and their receptors plexins and neuropilins, and how their crosstalk with oncogenic pathways in gliomas might modulate cancer progression. The emerging role of semaphorins and plexins as tumor suppressors or oncogenes is also discussed.
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Kwiatkowska A, Didier S, Fortin S, Chuang Y, White T, Berens ME, Rushing E, Eschbacher J, Tran NL, Chan A, Symons M. The small GTPase RhoG mediates glioblastoma cell invasion. Mol Cancer 2012; 11:65. [PMID: 22966858 PMCID: PMC3557187 DOI: 10.1186/1476-4598-11-65] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2012] [Accepted: 07/18/2012] [Indexed: 11/29/2022] Open
Abstract
Background The invasion of glioblastoma cells into regions of the normal brain is a critical factor that limits current therapies for malignant astrocytomas. Previous work has identified roles for the Rho family guanine nucleotide exchange factors Trio and Vav3 in glioblastoma invasion. Both Trio and Vav3 act on the small GTPase RhoG. We therefore examined the role of RhoG in the invasive behavior of glioblastoma cells. Results We found that siRNA-mediated depletion of RhoG strongly inhibits invasion of glioblastoma cells through brain slices ex vivo. In addition, depletion of RhoG has a marginal effect on glioblastoma cell proliferation, but significantly inhibits glioblastoma cell survival in colony formation assays. We also observed that RhoG is activated by both HGF and EGF, two factors that are thought to be clinically relevant drivers of glioblastoma invasive behavior, and that RhoG is overexpressed in human glioblastoma tumors versus non-neoplastic brain. In search of a mechanism for the contribution of RhoG to the malignant behavior of glioblastoma cells, we found that depletion of RhoG strongly inhibits activation of the Rac1 GTPase by both HGF and EGF. In line with this observation, we also show that RhoG contributes to the formation of lamellipodia and invadopodia, two functions that have been shown to be Rac1-dependent. Conclusions Our functional analysis of RhoG in the context of glioblastoma revealed a critical role for RhoG in tumor cell invasion and survival. These results suggest that targeting RhoG-mediated signaling presents a novel avenue for glioblastoma therapy.
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Affiliation(s)
- Aneta Kwiatkowska
- Center for Oncology and Cell Biology, The Feinstein Institute for Medical Research at North Shore-LIJ, Manhasset, NY, USA
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Surati M, Patel P, Peterson A, Salgia R. Role of MetMAb (OA-5D5) in c-MET active lung malignancies. Expert Opin Biol Ther 2012; 11:1655-62. [PMID: 22047509 DOI: 10.1517/14712598.2011.626762] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION MetMAb (OA-5D5) is a one-armed monoclonal antibody developed to bind to and inhibit c-MET receptor tyrosine kinase. Though only in early clinical testing, this agent holds great promise in diseases thought to be driven by c-MET activation, as evidenced by the Phase II results in NSCLC where a benefit in overall survival was observed in patients with MET-diagnostic-positive disease. Thus far, both alone and in combination with other targeted agents, this drug has been well tolerated and no new significant safety signals have been identified. AREAS COVERED This review summarizes the structure and function of the c-MET receptor and its ligand hepatic growth factor (HGF), provides an overview of select targeted monotherapies developed to interfere in the MET-HGF signaling pathway, discusses pre-clinical and clinical data surrounding MetMAb, and concludes with an expert opinion regarding this novel agent. EXPERT OPINION MetMAb has been well tolerated and based on Phase II data testing it, in combination with erlotinib in advanced NSCLC, may have a role in improving survival in patients with disease driven by c-MET activation. However, Phase III validation is underway and the results of these studies will help elucidate which patients will benefit most from this novel agent.
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Affiliation(s)
- Mosmi Surati
- University of Chicago, Pritzker School of Medicine, Chicago, IL 60637, USA
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36
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Chi AS, Batchelor TT, Kwak EL, Clark JW, Wang DL, Wilner KD, Louis DN, Iafrate AJ. Rapid Radiographic and Clinical Improvement After Treatment of a MET-Amplified Recurrent Glioblastoma With a Mesenchymal-Epithelial Transition Inhibitor. J Clin Oncol 2012; 30:e30-3. [DOI: 10.1200/jco.2011.38.4586] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Affiliation(s)
- Andrew S. Chi
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
| | - Tracy T. Batchelor
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
| | - Eunice L. Kwak
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
| | - Jeffrey W. Clark
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
| | - Daphne L. Wang
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
| | | | - David N. Louis
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
| | - A. John Iafrate
- Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA
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Accumulative copy number increase of MET drives tumor development and histological progression in a subset of ovarian clear-cell adenocarcinomas. Mod Pathol 2012; 25:122-30. [PMID: 21983935 DOI: 10.1038/modpathol.2011.143] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Our previous study demonstrated that, among ovarian carcinomas, amplification of the MET gene and overexpression of MET specifically and commonly occur in clear-cell adenocarcinoma histology. This study was conducted to address how these alterations contribute to development and progression of this highly chemoresistant form of ovarian cancer. We histologically reviewed 21 previously described MET amplification-positive clear-cell adenocarcinoma cases, and selected 11 tumors with synchronous endometriosis and 2 tumors with adjacent clear-cell adenofibroma (CCAF) components. Using double in situ hybridization and immunohistochemistry, copy number alterations of the MET gene and levels of MET protein expression were analyzed in these putative precursor lesions and the corresponding invasive carcinoma components in this selected cohort. All of the non-atypical precursor lesions analyzed (ie, non-atypical endometrioses and the benign CCAFs) were negative for MET gain. However, low-level (≥3 MET copies in ≥10% and ≥4 MET copies in 10-40% of tumor cells) gain of MET was detected in 4 (40%) of the 10 atypical endometrioses and 1 of the 2 borderline CCAFs. Moreover, high-level (≥4 MET copies in ≥40% of tumor cells) gain of MET were detected in five (50%) of the atypical endometrioses. In 4 (31%) of the 13 cases enrolled, intratumoral heterogeneity for MET gain was documented in invasive carcinoma components, wherein all the relatively differentiated carcinoma components showed low-level gain of MET and all the corresponding poorly differentiated carcinomas showed high-level gain. The overall incidence of MET overexpression gradually increased from the precursors of non-atypical form (0%), through those of atypical form (67%) and the relatively differentiated carcinoma components (92%), to the poorly differentiated carcinoma components (100%). These results suggest that accumulative MET gene copy number alterations causing MET overexpression are associated with higher tumor grade and might drive the development and progression of the MET amplification-positive ovarian clear-cell adenocarcinoma.
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38
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Sathornsumetee S, Rich JN. Molecularly targeted therapy in neuro-oncology. HANDBOOK OF CLINICAL NEUROLOGY 2012; 104:255-78. [PMID: 22230448 DOI: 10.1016/b978-0-444-52138-5.00018-9] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Affiliation(s)
- Andrew S Chi
- Department of Neurology, Massachusetts General Hospital, Boston, MA, USA
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40
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Guessous F, Yang Y, Johnson E, Marcinkiewicz L, Smith M, Zhang Y, Kofman A, Schiff D, Christensen J, Abounader R. Cooperation between c-Met and focal adhesion kinase family members in medulloblastoma and implications for therapy. Mol Cancer Ther 2011; 11:288-97. [PMID: 22188814 DOI: 10.1158/1535-7163.mct-11-0490] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
We previously showed the involvement of the tyrosine kinase receptor c-Met in medulloblastoma malignancy. The nonreceptor tyrosine kinases focal adhesion kinase (FAK) and Pyk2 are key players in the progression of different cancers. However, their role in medulloblastoma malignancy is not well understood. In this study, using a protein array approach, we found that c-Met induces FAK and Pyk2 phosphorylation in medulloblastoma cells. We therefore studied the interactions between c-Met and FAK/Pyk2 and their implications for medulloblastoma therapy. We found that c-Met activates FAK and Pyk2 in several medulloblastoma cell lines. We also found that FAK and Pyk2 mediate the malignant effects of c-Met on medulloblastoma cell proliferation, migration, and invasion. On the basis of these findings, we hypothesized that combined c-Met and FAK inhibitions would have additive effects on the inhibition of medulloblastoma malignancy. To test this hypothesis, we assessed the effects on medulloblastoma malignancy parameters of single or combined treatments of medulloblastoma cells with c-Met and FAK small-molecule kinase inhibitors. We found a significant increase in the inhibitory effect of both inhibitors on medulloblastoma cell migration and cell invasion as compared with single inhibitions (P < 0.05). In addition, oral gavage treatment with c-Met inhibitor of mice bearing medulloblastoma xenografts significantly reduced in vivo tumor growth. Therefore, combining c-Met inhibitors with FAK inhibitors constitutes a new potential strategy for medulloblastoma therapy. Altogether, our study describes a role for FAK and Pyk2 in medulloblastoma malignancy, uncovers new interactions between c-Met and FAK/Pyk2, and proposes for the first time combining anti-c-Met and anti-FAK inhibitors as a new strategy for medulloblastoma therapy.
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Affiliation(s)
- Fadila Guessous
- Department of Microbiology, University of Virginia, Charlottesville, VA 22908, USA
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41
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Kwak IH, Shin YH, Kim M, Cha HY, Nam HJ, Lee BS, Chaudhary SC, Pai KS, Lee JH. Epigallocatechin-3-gallate inhibits paracrine and autocrine hepatocyte growth factor/scatter factor-induced tumor cell migration and invasion. Exp Mol Med 2011; 43:111-20. [PMID: 21209554 DOI: 10.3858/emm.2011.43.2.013] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Aberrant activation of hepatocyte growth factor/scatter factor (HGF/SF) and its receptor, Met, is involved in the development and progression of many human cancers. In the cell-based screening assay, (-)epigallocatechin-3-gallate (EGCG) inhibited HGF/SF-Met signaling as indicated by its inhibitory activity on HGF/SF-induced cell scattering and uPA activation (IC50=15.8 microgram/ml). Further analysis revealed that EGCG at low doses specifically inhibited HGF/SF-induced tyrosine phosphorylation of Met but not epidermal growth factor (EGF)-induced phosphorylation of EGF receptor (EGFR). On the other hand, high-dose EGCG decreased both Met and EGFR proteins. We also found that EGCG did not act on the intracellular portion of Met receptor tyrosine kinase, i.e., it inhibited InlB-dependent activation of Met but not NGF-induced activation of Trk-Met hybrid receptor. This inhibition decreased HGF-induced migration and invasion by parental or HGF/SF-transfected B16F10 melanoma cells in vitro in either a paracrine or autocrine manner. Furthermore, EGCG inhibited the invasion/metastasis of HGF/SF-transfected B16F10 melanoma cells in mice. Our data suggest the possible use of EGCG in human cancers associated with dysregulated paracrine or autocrine HGF/SF-Met signaling.
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Affiliation(s)
- In-hae Kwak
- Department of Biochemistry, Ajou University Medical School, Suwon, Korea
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Toschi L, Cappuzzo F. Clinical implications of MET gene copy number in lung cancer. Future Oncol 2010; 6:239-47. [PMID: 20146583 DOI: 10.2217/fon.09.164] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
MET, the receptor for HGF, has recently been identified as a novel promising target in several human malignancies, including non-small-cell lung cancer (NSCLC). Deregulation of the HGF/MET signaling pathway can occur via different mechanisms, including HGF and/or MET overexpression, MET gene amplification, mutations or rearrangements. While the role of MET mutations in NSCLC is not yet fully understood, MET amplification emerged as a critical event in driving cell survival, with preclinical data suggesting that MET-amplified cell lines are exquisitely sensitive to MET inhibition. True MET amplification, which has been associated with poor prognosis in different retrospective series, is a relatively uncommon event in NSCLC, occurring in 1-7% of unselected cases. Nevertheless, in highly selected cohorts of patients, such as those harboring somatic mutations of the EGF receptor (EGFR) with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs), MET amplification can be observed in up to 20% of cases. Preclinical data suggested that a treatment approach including a combination of EGFR and MET TKIs could be an effective strategy in this setting and led to the clinical investigation of multiple MET TKIs in combination with erlotinib. Results from ongoing and future trials will clarify the role of MET TKIs for the treatment of NSCLC and will provide insights into the most appropriate timing for their use.
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Affiliation(s)
- Luca Toschi
- Dana-Farber Cancer Institute, Boston, MA 02215, USA.
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Goodwin CR, Lal B, Zhou X, Ho S, Xia S, Taeger A, Murray J, Laterra J. Cyr61 mediates hepatocyte growth factor-dependent tumor cell growth, migration, and Akt activation. Cancer Res 2010; 70:2932-41. [PMID: 20233866 DOI: 10.1158/0008-5472.can-09-3570] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Certain tumor cell responses to the growth factor-inducible early response gene product CCN1/Cyr61 overlap with those induced by the hepatocyte growth factor (HGF)/c-Met signaling pathway. In this study, we investigate if Cyr61 is a downstream effector of HGF/c-Met pathway activation in human glioma cells. A semiquantitative immunohistochemical analysis of 112 human glioma and normal brain specimens showed that levels of tumor-associated Cyr61 protein correlate with tumor grade (P < 0.001) and with c-Met protein expression (r(2) = 0.4791, P < 0.0001). Purified HGF rapidly upregulated Cyr61 mRNA (peak at 30 minutes) and protein expression (peak at 2 hours) in HGF(-)/c-Met(+) human glioma cell lines via a transcription- and translation-dependent mechanism. Conversely, HGF/c-Met pathway inhibitors reduced Cyr61 expression in HGF(+)/c-Met(+) human glioma cell lines in vitro and in HGF(+)/c-Met(+) glioma xenografts. Targeting Cyr61 expression with small interfering RNA (siRNA) inhibited HGF-induced cell migration (P < 0.01) and cell growth (P < 0.001) in vitro. The effect of Cyr61 on HGF-induced Akt pathway activation was also examined. Cyr61 siRNA had no effect on the early phase of HGF-induced Akt phosphorylation (Ser(473)) 30 minutes after stimulation with HGF. Cyr61 siRNA inhibited a second phase of Akt phosphorylation measured 12 hours after cell stimulation with HGF and also inhibited HGF-induced phosphorylation of the Akt target glycogen synthase kinase 3alpha. We treated preestablished subcutaneous glioma xenografts with Cyr61 siRNA or control siRNA by direct intratumoral delivery. Cyr61 siRNA inhibited Cyr61 expression and glioma xenograft growth by up to 40% in a dose-dependent manner (P < 0.05). These results identify a Cyr61-dependent pathway by which c-Met activation mediates cell growth, cell migration, and long-lasting signaling events in glioma cell lines and possibly astroglial malignancies.
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Affiliation(s)
- C Rory Goodwin
- Kennedy Krieger Institute, Johns Hopkins School of Medicine, Baltimore, MD, USA
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Guessous F, Zhang Y, Kofman A, Catania A, Li Y, Schiff D, Purow B, Abounader R. microRNA-34a is tumor suppressive in brain tumors and glioma stem cells. Cell Cycle 2010; 9:1031-6. [PMID: 20190569 DOI: 10.4161/cc.9.6.10987] [Citation(s) in RCA: 247] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
We recently found that microRNA-34a (miR-34a) is downregulated in human glioma tumors as compared to normal brain, and that miR-34a levels in mutant-p53 gliomas were lower than in wildtype-p53 tumors. We showed that miR-34a expression in glioma and medulloblastoma cells inhibits cell proliferation, G1/S cell cycle progression, cell survival, cell migration and cell invasion, but that miR-34a expression in human astrocytes does not affect cell survival and cell cycle. We uncovered the oncogenes c-Met, Notch-1 and Notch-2 as direct targets of miR-34a that are inhibited by miR-34a transfection. We found that c-Met levels in human glioma specimens inversely correlate with miR-34a levels. We showed that c-Met and Notch partially mediate the inhibitory effects of miR-34a on cell proliferation and cell death. We also found that mir-34a expression inhibits in vivo glioma xenograft growth. We concluded that miR-34a is a potential tumor suppressor in brain tumors that acts by targeting multiple oncogenes. In this extra view, we briefly review and discuss the implications of these findings and present new data on the effects of miR-34a in glioma stem cells. The new data show that miR-34a expression inhibits various malignancy endpoints in glioma stem cells. Importantly, they also show for the first time that miR-34a expression induces glioma stem cell differentiation. Altogether, the data suggest that miR-34a is a tumor suppressor and a potential potent therapeutic agent that acts by targeting multiple oncogenic pathways in brain tumors and by inducing the differentiation of cancer stem cells.
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Affiliation(s)
- Fadila Guessous
- Department of Microbiology, University of Virginia, Charlottesville, VA, USA
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45
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Goetsch L, Caussanel V. Selection criteria for c-Met-targeted therapies: emerging evidence for biomarkers. Biomark Med 2010; 4:149-70. [DOI: 10.2217/bmm.09.67] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Extensive development of targeted therapies emphasize the critical need for biomarkers and major efforts have been engaged to identify screening, prognostic, stratification and therapy-monitoring markers. One of the challenges in translating preclinical studies into effective clinical therapies remains the accurate identification of a responsive subsets of patients. Studies on trastuzumab demonstrated that patient response could be specifically correlated with the amplification of the Her2 gene. However, for the EGF receptor, it has been more difficult to find the right stratification biomarker and recent data demonstrate that genetic alterations for the EGF receptor have to be considered. Taken together, these data underline the need for a deeper understanding of both targeted receptor and human disease to determine pathways that might be investigated during early clinical trials in order to define relevant biomarkers for patient selection. This article, dealing with the c-Met tyrosine kinase receptor, provides an overview of c-Met alterations observed in cancer and proposes approaches for stratification biomarker selection.
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Affiliation(s)
- Liliane Goetsch
- Centre d’Immunologie Pierre Fabre, 5 avenue Napoléon III F-74164 Saint Julien en Genevois, France
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46
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Hepatocyte growth factor in cerebrospinal fluid is associated with mortality and recurrence of glioblastoma, and could be of prognostic value. J Neurooncol 2009; 97:347-51. [PMID: 19856144 DOI: 10.1007/s11060-009-0037-8] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2009] [Accepted: 10/12/2009] [Indexed: 10/20/2022]
Abstract
Malignant gliomas--glioblastoma multiforme and anaplastic astrocytoma--are among the most fatal forms of cancer in humans. It has been suggested that hepatocyte growth factor (HGF) is a reliable predictor of glioma malignancy; amounts of HGF are directly related to cellular proliferation, angiogenesis, low apoptotic rate, and poor prognosis (WHO III and IV). We measured the HGF content of cerebrospinal fluid (CSF) from patients with malignant glioma glioblastoma multiforme (WHO IV; n = 14), anaplastic astrocytoma (WHO III; n = 4), and meningioma (WHO I; n = 9), and from control subjects (n = 25), and found a high concentration of HGF in patients with malignant glioma. However, CSF concentrations from glioblastoma multiforme and anaplastic astrocytoma patients were not statistically significantly different (893 +/- 157 vs. 728 +/- 61, respectively; P > 0.01). A negative correlation between HGF and survival was found at five years of follow-up (R = -0.922, R (2) = 0.850, P < 0.001). Also, the HGF concentration in CSF was a reliable means of explaining the highly variable survival of patients with malignant glioma. CSF concentrations of HGF higher than 500 pg/ml were associated with increased mortality whereas values higher than 850 pg/ml were associated with a brief tumor-free period after surgery (9 +/- 0.6 vs. 6 +/- 0.6 months, respectively, P < 0.001). Our findings support the idea that measurement of HGF in CSF could be a useful tool for monitoring the biological activity of malignant glioma. The findings will ultimately need to be confirmed in a much larger study.
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Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R. MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. Cancer Res 2009; 69:7569-76. [PMID: 19773441 DOI: 10.1158/0008-5472.can-09-0529] [Citation(s) in RCA: 473] [Impact Index Per Article: 29.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
MicroRNA-34a (miR-34a) is a transcriptional target of p53 that is down-regulated in some cancer cell lines. We studied the expression, targets, and functional effects of miR-34a in brain tumor cells and human gliomas. Transfection of miR-34a down-regulated c-Met in human glioma and medulloblastoma cells and Notch-1, Notch-2, and CDK6 protein expressions in glioma cells. miR-34a expression inhibited c-Met reporter activities in glioma and medulloblastoma cells and Notch-1 and Notch-2 3'-untranslated region reporter activities in glioma cells and stem cells. Analysis of human specimens showed that miR-34a expression is down-regulated in glioblastoma tissues as compared with normal brain and in mutant p53 gliomas as compared with wild-type p53 gliomas. miR-34a levels in human gliomas inversely correlated to c-Met levels measured in the same tumors. Transient transfection of miR-34a into glioma and medulloblastoma cell lines strongly inhibited cell proliferation, cell cycle progression, cell survival, and cell invasion, but transfection of miR-34a into human astrocytes did not affect cell survival and cell cycle status. Forced expression of c-Met or Notch-1/Notch-2 transcripts lacking the 3'-untranslated region sequences partially reversed the effects of miR-34a on cell cycle arrest and cell death in glioma cells and stem cells, respectively. Also, transient expression of miR-34a in glioblastoma cells strongly inhibited in vivo glioma xenograft growth. Together, these findings represent the first comprehensive analysis of the role of miR-34a in gliomas. They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors.
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Affiliation(s)
- Yunqing Li
- Departments of Microbiology, Neurology and Pathology, University of Virginia, Charlottesville, VA 22908, USA
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MET receptor tyrosine kinase as a therapeutic anticancer target. Cancer Lett 2009; 280:1-14. [DOI: 10.1016/j.canlet.2008.10.045] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2008] [Revised: 10/24/2008] [Accepted: 10/24/2008] [Indexed: 12/23/2022]
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Naran S, Zhang X, Hughes SJ. Inhibition of HGF/MET as therapy for malignancy. Expert Opin Ther Targets 2009; 13:569-81. [DOI: 10.1517/14728220902853917] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Abounader R. Interactions between PTEN and receptor tyrosine kinase pathways and their implications for glioma therapy. Expert Rev Anticancer Ther 2009; 9:235-45. [PMID: 19192961 DOI: 10.1586/14737140.9.2.235] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Gliomas are the most common and deadly form of malignant primary brain tumors. Loss of the tumor-suppressor PTEN and activation of the receptor tyrosine kinases (RTKs) EGF receptor, c-Met, PDGF receptor and VEGF receptor are among the most common molecular dysfunctions associated with glioma malignancy. PTEN interacts with RTK-dependent signaling at multiple levels. These include the ability of PTEN to counteract PI3K activation by RTKs, as well as possible effects of PTEN on RTK activation of the MAPK pathway and RTK-dependent gene-expression regulation. Consequently, PTEN expression affects RTK-induced malignancy. Importantly, the PTEN status was recently found to be critical for the outcome of RTK-targeted clinical therapies that have been developed recently. Combining RTK-targeted therapies with therapies aimed at counteracting the effects of PTEN loss, such as mTOR inhibition, might also have therapeutic advantage. This article reviews the known molecular and functional interactions between PTEN and RTK pathways and their implications for glioma therapy.
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Affiliation(s)
- Roger Abounader
- Departments of Neurology and Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA.
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