|
1
|
Mohan CD, Shanmugam MK, Gowda SGS, Chinnathambi A, Rangappa KS, Sethi G. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155379. [PMID: 38503157 DOI: 10.1016/j.phymed.2024.155379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
Collapse
Affiliation(s)
- Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226 001, India
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kanchugarakoppal S Rangappa
- Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
| |
Collapse
|
|
2
|
Chen F, Zhang W, Gao X, Yuan H, Liu K. The Role of Small Interfering RNAs in Hepatocellular Carcinoma. J Gastrointest Cancer 2024; 55:26-40. [PMID: 37432548 DOI: 10.1007/s12029-023-00911-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2023] [Indexed: 07/12/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC), a primary liver cancer with high mortality, is the most common malignant tumor in the world. Currently, the effect of routine treatment is poor, especially for this kind of cancer with strong heterogeneity and late detection. In the past decades, the researches of gene therapy for HCC based on small interfering RNA have blossomed everywhere. This is a promising therapeutic strategy, but the application of siRNA is limited by the discovery of effective molecular targets and the delivery system targeting HCC. As the deepening of research, scientists have developed many effective delivery systems and found more new therapeutic targets. CONCLUSIONS This paper mainly reviews the research on HCC treatment based on siRNA in recent years, and summarizes and classifies the HCC treatment targets and siRNA delivery systems.
Collapse
Affiliation(s)
- Feng Chen
- Department of Biopharmaceutical, Shanghai Ocean University, Shanghai, 201306, China
| | - Wang Zhang
- Department of Biopharmaceutical, Shanghai Ocean University, Shanghai, 201306, China
| | - Xinran Gao
- Department of Biopharmaceutical, Shanghai Ocean University, Shanghai, 201306, China
| | - Hui Yuan
- Department of Biopharmaceutical, Shanghai Ocean University, Shanghai, 201306, China
| | - Kehai Liu
- Department of Biopharmaceutical, Shanghai Ocean University, Shanghai, 201306, China.
| |
Collapse
|
|
3
|
Xia ZY, Liu L, Kuok CF, Wang XL, Shi D, Ma Q, Cheng XY, Wang GL, Li MJ, Zheng QS, Liu XN, Li DF, Li BH. Loureirin A Promotes Cell Differentiation and Suppresses Migration and Invasion of Melanoma Cells via WNT and AKT/mTOR Signaling Pathways. Biol Pharm Bull 2024; 47:486-498. [PMID: 38199251 DOI: 10.1248/bpb.b23-00415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2024]
Abstract
Resina Draconis is a traditional Chinese medicine, with the in-depth research, its medicinal value in anti-tumor has been revealed. Loureirin A is extracted from Resina Draconis, however, research on the anti-tumor efficacy of Loureirin A is rare. Herein, we investigated the function of Loureirin A in melanoma. Our research demonstrated that Loureirin A inhibited the proliferation of and caused G0/G1 cell cycle arrest in melanoma cells in a concentration-dependent manner. Further study showed that the melanin content and tyrosinase activity was enhanced after Loureirin A treatment, demonstrated that Loureirin A promoted melanoma cell differentiation, which was accompanied with the reduce of WNT signaling pathway. Meanwhile, we found that Loureirin A suppressed the migration and invasion of melanoma cells through the protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway. Taken together, this study demonstrated for the first time the anti-tumor effects of Loureirin A in melanoma cells, which provided a novel therapeutic strategy against melanoma.
Collapse
Affiliation(s)
- Zi-Yi Xia
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Ling Liu
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Chiu-Fai Kuok
- Faculty of Health Sciences and Sports, Macao Polytechnic University
| | - Xue-Li Wang
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Dan Shi
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Quan Ma
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Xiao-Yang Cheng
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Guo-Li Wang
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Min-Jing Li
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Qiu-Sheng Zheng
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Xiao-Na Liu
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - De-Fang Li
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| | - Bo-Han Li
- Featured Laboratory for Biosynthesis and Target Discovery of Active Components of Traditional Chinese Medicine, School of Integrated Traditional Chinese and Western Medicine, Binzhou Medical University
| |
Collapse
|
|
4
|
Zhou Y, Rasner CJ, Giubellino A. MACC1 and MET as markers associated with progression and metastasis in cutaneous melanoma. Front Oncol 2023; 13:1146092. [PMID: 37496665 PMCID: PMC10365967 DOI: 10.3389/fonc.2023.1146092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 06/23/2023] [Indexed: 07/28/2023] Open
Abstract
Cutaneous melanoma is the most common lethal malignancy among skin cancers and has a high propensity for metastasis. Understanding the mechanisms governing tumorigenesis, progression and metastasis as well as identifying biomarkers guiding risk stratification and management of the disease is essential. MACC1 has been found to play key roles in cancer cell migration, invasion, epithelial-to-mesenchymal transition, and metastasis in various types of cancer, through activation of MET signaling. In this study, we examined the extent of MACC1 and MET protein expression by immunohistochemical staining in a tissue microarray constructed from twenty-three melanomas and ten melanocytic nevi. We observed significantly higher levels of MACC1 expression on average in metastatic melanomas, comparing to primary melanomas and nevi. MET expression in metastatic melanomas was also significantly higher than in nevi. MACC1 expression does not appear to correlate with MET expression in nevi and primary melanomas. However, this correlation appears stronger in metastatic melanomas, where seven (78%) of nine cases show intermediate to high expression of both MACC1 and MET. The expressions of MACC1 and MET do not show significant differences based on other clinicopathologic factors including patient age, gender, histologic subtypes, depth of invasion, and staging. Our study suggests that high expression of MACC1 or both MACC1 and MET is associated with metastasis of cutaneous melanoma.
Collapse
Affiliation(s)
- Yan Zhou
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States
| | - Cody J. Rasner
- Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN, United States
| | - Alessio Giubellino
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, United States
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, United States
| |
Collapse
|
|
5
|
Shah PD, Huang AC, Xu X, Orlowski R, Amaravadi RK, Schuchter LM, Zhang P, Tchou J, Matlawski T, Cervini A, Shea J, Gilmore J, Lledo L, Dengel K, Marshall A, Wherry EJ, Linette GP, Brennan A, Gonzalez V, Kulikovskaya I, Lacey SF, Plesa G, June CH, Vonderheide RH, Mitchell TC. Phase I Trial of Autologous RNA-electroporated cMET-directed CAR T Cells Administered Intravenously in Patients with Melanoma and Breast Carcinoma. CANCER RESEARCH COMMUNICATIONS 2023; 3:821-829. [PMID: 37377890 PMCID: PMC10167933 DOI: 10.1158/2767-9764.crc-22-0486] [Citation(s) in RCA: 39] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 03/24/2023] [Accepted: 03/28/2023] [Indexed: 06/29/2023]
Abstract
Purpose Treatments are limited for metastatic melanoma and metastatic triple-negative breast cancer (mTNBC). This pilot phase I trial (NCT03060356) examined the safety and feasibility of intravenous RNA-electroporated chimeric antigen receptor (CAR) T cells targeting the cell-surface antigen cMET. Experimental Design Metastatic melanoma or mTNBC subjects had at least 30% tumor expression of cMET, measurable disease and progression on prior therapy. Patients received up to six infusions (1 × 10e8 T cells/dose) of CAR T cells without lymphodepleting chemotherapy. Forty-eight percent of prescreened subjects met the cMET expression threshold. Seven (3 metastatic melanoma, 4 mTNBC) were treated. Results Mean age was 50 years (35-64); median Eastern Cooperative Oncology Group 0 (0-1); median prior lines of chemotherapy/immunotherapy were 4/0 for TNBC and 1/3 for melanoma subjects. Six patients experienced grade 1 or 2 toxicity. Toxicities in at least 1 patient included anemia, fatigue, and malaise. One subject had grade 1 cytokine release syndrome. No grade 3 or higher toxicity, neurotoxicity, or treatment discontinuation occurred. Best response was stable disease in 4 and disease progression in 3 subjects. mRNA signals corresponding to CAR T cells were detected by RT-PCR in all patients' blood including in 3 subjects on day +1 (no infusion administered on this day). Five subjects underwent postinfusion biopsy with no CAR T-cell signals seen in tumor. Three subjects had paired tumor tissue; IHC showed increases in CD8 and CD3 and decreases in pS6 and Ki67. Conclusions Intravenous administration of RNA-electroporated cMET-directed CAR T cells is safe and feasible. Significance Data evaluating CAR T therapy in patients with solid tumors are limited. This pilot clinical trial demonstrates that intravenous cMET-directed CAR T-cell therapy is safe and feasible in patients with metastatic melanoma and metastatic breast cancer, supporting the continued evaluation of cellular therapy for patients with these malignancies.
Collapse
Affiliation(s)
- Payal D. Shah
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Alexander C. Huang
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xiaowei Xu
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert Orlowski
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Ravi K. Amaravadi
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lynn M. Schuchter
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Paul Zhang
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Julia Tchou
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Tina Matlawski
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Amanda Cervini
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joanne Shea
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Joan Gilmore
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lester Lledo
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Karen Dengel
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Amy Marshall
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - E. John Wherry
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Department of Systems Pharmacology and Translational Therapeutics, Institute of Immunology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gerald P. Linette
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Andrea Brennan
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Vanessa Gonzalez
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Irina Kulikovskaya
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Simon F. Lacey
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Gabriela Plesa
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Carl H. June
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert H. Vonderheide
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Tara C. Mitchell
- Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| |
Collapse
|
|
6
|
Koo K, Wuenschmann A, Rendahl A, Song KY, Forster C, Wolf-Ringwall A, Borgatti A, Giubellino A. Expression and Prognostic Evaluation of the Receptor Tyrosine Kinase MET in Canine Malignant Melanoma. Vet Sci 2023; 10:vetsci10040249. [PMID: 37104404 PMCID: PMC10144085 DOI: 10.3390/vetsci10040249] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2023] [Revised: 03/21/2023] [Accepted: 03/23/2023] [Indexed: 03/29/2023] Open
Abstract
The overexpression and activation of the MET receptor tyrosine kinase has been identified in many human malignancies, but its role in canine cancer has only been minimally investigated. In this study we evaluated the expression of MET in two canine malignant melanoma (CMM) cell lines as well as in 30 CMM tissue samples that were collected from the clinical service at our institution. We were able to confirm the expression of the MET protein in both melanoma cell lines, and we demonstrated MET activation by its ligand, HGF, through phosphorylation, in Western blot analysis. We were also able to demonstrate, by immunohistochemistry, the expression of MET in 63% of the tumor tissue samples analyzed, with the majority demonstrating a relatively low expression profile. We then evaluated the association of MET expression scores with histologic parameters, metastasis, and survival. While statistically significant associations were not found across these parameters, an inverse relationship between MET expression levels and time to lymph node versus distant metastasis was suggested in our cohort. These findings may require assessment in a larger group of specimens to further evaluate the role of MET expression in the homing of metastasis in lymph nodes versus that in distant organs.
Collapse
|
|
7
|
Lei X, Zhang Y, Mao L, Jiang P, Huang Y, Gu J, Tai N. Prognostic value of receptor tyrosine kinases in malignant melanoma patients: A systematic review and meta-analysis of immunohistochemistry. Front Oncol 2022; 12:819051. [PMID: 36212475 PMCID: PMC9538722 DOI: 10.3389/fonc.2022.819051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 09/01/2022] [Indexed: 12/02/2022] Open
Abstract
Background Substantial evidence suggests that receptor tyrosine kinases (RTKs) are overexpressed in tumors; however, few studies have focused on the prognostic value of RTKs in melanoma. Objectives The objective of this study is to evaluate the association between overexpression of RTKs and survival in melanoma patients based on immunohistochemistry (IHC) analysis. Methods Our review is registered on PROSPERO (http://www.crd.york.ac.uk/PROSPERO), registration number CRD42021261460. Seven databases were searched, and data were extracted. We used IHC to measure the association between overexpression of RTKs and overall survival (OS), disease-free survival (DFS), progression-free survival (PFS), and clinicopathology in melanoma patients. Pooled analysis was conducted to assess the differences between Hazard Ratios along with 95% confidence intervals. Results Of 5,508 publications examined following the database search, 23 publications were included in this study, which included data from a total of 2,072 patients. Vascular endothelial growth factor receptor 2 (VEGF-R2) overexpression was associated with worse OS and DFS in melanoma. Furthermore, there was an association between OS and the expression of several RTKs, including epidermal growth factor receptor (EGFR), mesenchymal-epithelial transition factor (MET), vascular endothelial growth factor receptor 1 (VEGF-R1), and insulin-like growth factor 1 receptor (IGF-1R). There were no significant correlations between EGFR overexpression and worse DFS or PFS. EGFR overexpression was associated with worse OS cutaneous and nasal melanoma, but not uveal melanoma. However, MET overexpression was related to worse OS in both cutaneous and uveal melanoma. Furthermore, EGFR overexpression was associated with a worse OS in Europe compared to other geographic areas. Moreover, EGFR and MET overexpression showed significant prognostic value in patients with the cut-off “≥10% staining”. Conclusions Our findings build concrete evidence that overexpression of RTKs is associated with poor prognosis and clinicopathology in melanoma, highlighting RTK expression has the potential to inform individualized combination therapies and accurate prognostic evaluation.
Collapse
Affiliation(s)
- Xuan Lei
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yiming Zhang
- Department of Orthopedics, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Lianghao Mao
- Department of Orthopedics, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Pan Jiang
- Department of Orthopedics, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Yumeng Huang
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Jia Gu
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Ningzheng Tai
- Department of Burns and Plastic Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
- *Correspondence: Ningzheng Tai,
| |
Collapse
|
|
8
|
Treatment of Metastatic Melanoma with a Combination of Immunotherapies and Molecularly Targeted Therapies. Cancers (Basel) 2022; 14:cancers14153779. [PMID: 35954441 PMCID: PMC9367420 DOI: 10.3390/cancers14153779] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Revised: 07/02/2022] [Accepted: 07/19/2022] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Immunotherapies and molecularly targeted therapies have drastically changed the therapeutic approach for unresectable advanced or metastatic melanoma. The majority of melanoma patients have benefitted from these therapies; however, some patients acquire resistance to them. Novel combinations of immunotherapies and molecularly targeted therapies may be more efficient in treating these patients. In this review, we discuss various combination therapies under pre-clinical and clinical development which can reduce toxicity, enhance efficacy, and prevent recurrences in patients with metastatic melanoma. Abstract Melanoma possesses invasive metastatic growth patterns and is one of the most aggressive types of skin cancer. In 2021, it is estimated that 7180 deaths were attributed to melanoma in the United States alone. Once melanoma metastasizes, traditional therapies are no longer effective. Instead, immunotherapies, such as ipilimumab, pembrolizumab, and nivolumab, are the treatment options for malignant melanoma. Several biomarkers involved in tumorigenesis have been identified as potential targets for molecularly targeted melanoma therapy, such as tyrosine kinase inhibitors (TKIs). Unfortunately, melanoma quickly acquires resistance to these molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been employed and have been shown to improve the prognosis of melanoma patients compared to monotherapy. This review discusses several combination therapies that target melanoma biomarkers, such as BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K. Several of these regimens are already FDA-approved for treating metastatic melanoma, while others are still in clinical trials. Continued research into the causes of resistance and factors influencing the efficacy of these combination treatments, such as specific mutations in oncogenic proteins, may further improve the effectiveness of combination therapies, providing a better prognosis for melanoma patients.
Collapse
|
|
9
|
Zheng H, Fu Q, Ma K, Shi S, Fu Y. Circ_0079558 promotes papillary thyroid cancer progression by binding to miR-26b-5p to activate MET/AKT signaling. Endocr J 2021; 68:1247-1266. [PMID: 34565758 DOI: 10.1507/endocrj.ej20-0498] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022] Open
Abstract
Circular RNAs (circRNAs) are a group of non-coding RNAs featured by covalently closed circular structure. CircRNA_0079558 (circ_0079558) is derived from RAPGEF5 gene, and it has been found to be significantly up-regulated in papillary thyroid carcinoma (PTC). However, the role and working mechanism of circ_0079558 in PTC progression have never been illustrated. The levels of circ_0079558 and MET proto-oncogene, receptor tyrosine kinase (MET) were up-regulated in PTC tissues and cell lines, as evidenced by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and Western blot assay. The silencing of circ_0079558 or MET restrained cell proliferation, migration and invasion whereas triggered cell apoptosis in PTC cells, as verified by Cell Counting Kit-8 (CCK8) assay, plate colony formation assay, transwell invasion assay, wound healing assay and flow cytometry. Through using MET specific inhibitor PHA665752, we found that circ_0079558 overexpression enhanced the malignant behaviors of PTC cells through activating MET/AKT pathway. Through dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay, microRNA-26b-5p (miR-26b-5p) was identified to be the intermediary molecular between circ_0079558 and MET, and circ_0079558 knockdown reduced the expression of MET partly through elevating miR-26b-5p in PTC cells. The miR-198/FGFR1 pathway was identified as another signal axis downstream of circ_0079558, and the co-overexpression of FGFR1 and MET largely rescued the proliferation ability of circ_0079558-silenced PTC cells. Through xenograft tumor model, we found that circ_0079558 silencing restrained xenograft tumor growth in vivo. In conclusion, circ_0079558 facilitated the proliferation and motility whereas inhibited the apoptosis of PTC cells largely through mediating miR-26b-5p/MET/AKT signaling.
Collapse
Affiliation(s)
- Haibo Zheng
- Department of Anesthesiology, The Second Hospital of Jilin University, Changchun, Jilin, China
| | - Qingfeng Fu
- Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China
| | - Kaili Ma
- Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China
| | - Shuai Shi
- Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China
| | - Yantao Fu
- Department of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Changchun, Jilin, China
| |
Collapse
|
|
10
|
Fu J, Su X, Li Z, Deng L, Liu X, Feng X, Peng J. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 2021; 40:4625-4651. [PMID: 34145400 DOI: 10.1038/s41388-021-01863-w] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal-epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.
Collapse
Affiliation(s)
- Jianjiang Fu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xiaorui Su
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Zhihua Li
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
- Department of Fetal Medicine and Prenatal Diagnosis, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ling Deng
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiawei Liu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xuancheng Feng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
| | - Juan Peng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
| |
Collapse
|
|
11
|
Singhal SS, Srivastava S, Mirzapoiazova T, Horne D, Awasthi S, Salgia R. Targeting the mercapturic acid pathway for the treatment of melanoma. Cancer Lett 2021; 518:10-22. [PMID: 34126193 DOI: 10.1016/j.canlet.2021.06.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 06/03/2021] [Accepted: 06/07/2021] [Indexed: 02/07/2023]
Abstract
The treatment of metastatic melanoma is greatly hampered by the simultaneous dysregulation of several major signaling pathways that suppress apoptosis and promote its growth and invasion. The global resistance of melanomas to therapeutics is also supported by a highly active mercapturic acid pathway (MAP), which is responsible for the metabolism and excretion of numerous chemotherapy agents. The relative importance of the MAP in melanoma survival was not recognized until demonstrated that B16 melanoma undergoes dramatic apoptosis and regression upon the depletion or inhibition of the MAP transporter protein RLIP. RLIP is a multi-functional protein that couples ATP hydrolysis with the movement of substances. As the rate-limiting step of the MAP, the primary function of RLIP in the plasma membrane is to catalyze the ATP-dependent efflux of unmetabolized drugs and toxins, including glutathione (GSH) conjugates of electrophilic toxins (GS-Es), which are the precursors of mercapturic acids. Clathrin-dependent endocytosis (CDE) is an essential mechanism for internalizing ligand-receptor complexes that promote tumor cell proliferation through autocrine stimulation (Wnt5a, PDGF, βFGF, TNFα) or paracrine stimulation by hormones produced by fibroblasts (IGF1, HGF) or inflammatory cells (IL8). Aberrant functioning of these pathways appears critical for melanoma cell invasion, metastasis, and evasion of apoptosis. This review focuses on the selective depletion or inhibition of RLIP as a highly effective targeted therapy for melanoma that could cause the simultaneous disruption of the MAP and critical peptide hormone signaling that relies on CDE.
Collapse
Affiliation(s)
- Sharad S Singhal
- Department of Medical Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA.
| | - Saumya Srivastava
- Department of Medical Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| | - Tamara Mirzapoiazova
- Department of Medical Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| | - David Horne
- Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| | - Sanjay Awasthi
- Department of Internal Medicine, Division of Hematology & Oncology, Texas Tech University Health Sciences Center, Lubbock, TX, 79430, USA
| | - Ravi Salgia
- Department of Medical Oncology, Beckman Research Institute, City of Hope Comprehensive Cancer Center and National Medical Center, Duarte, CA, 91010, USA
| |
Collapse
|
|
12
|
Sabbah M, Najem A, Krayem M, Awada A, Journe F, Ghanem GE. RTK Inhibitors in Melanoma: From Bench to Bedside. Cancers (Basel) 2021; 13:1685. [PMID: 33918490 PMCID: PMC8038208 DOI: 10.3390/cancers13071685] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/12/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023] Open
Abstract
MAPK (mitogen activated protein kinase) and PI3K/AKT (Phosphatidylinositol-3-Kinase and Protein Kinase B) pathways play a key role in melanoma progression and metastasis that are regulated by receptor tyrosine kinases (RTKs). Although RTKs are mutated in a small percentage of melanomas, several receptors were found up regulated/altered in various stages of melanoma initiation, progression, or metastasis. Targeting RTKs remains a significant challenge in melanoma, due to their variable expression across different melanoma stages of progression and among melanoma subtypes that consequently affect response to treatment and disease progression. In this review, we discuss in details the activation mechanism of several key RTKs: type III: c-KIT (mast/stem cell growth factor receptor); type I: EGFR (Epidermal growth factor receptor); type VIII: HGFR (hepatocyte growth factor receptor); type V: VEGFR (Vascular endothelial growth factor), structure variants, the function of their structural domains, and their alteration and its association with melanoma initiation and progression. Furthermore, several RTK inhibitors targeting the same receptor were tested alone or in combination with other therapies, yielding variable responses among different melanoma groups. Here, we classified RTK inhibitors by families and summarized all tested drugs in melanoma indicating the rationale behind the use of these drugs in each melanoma subgroups from preclinical studies to clinical trials with a specific focus on their purpose of treatment, resulted effect, and outcomes.
Collapse
Affiliation(s)
- Malak Sabbah
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ahmad Najem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Mohammad Krayem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ahmad Awada
- Medical Oncolgy Clinic, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium;
| | - Fabrice Journe
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| | - Ghanem E. Ghanem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium; (M.S.); (A.N.); (M.K.); (F.J.)
| |
Collapse
|
|
13
|
Resistance to Molecularly Targeted Therapies in Melanoma. Cancers (Basel) 2021; 13:cancers13051115. [PMID: 33807778 PMCID: PMC7961479 DOI: 10.3390/cancers13051115] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
Malignant melanoma is the most aggressive type of skin cancer with invasive growth patterns. In 2021, 106,110 patients are projected to be diagnosed with melanoma, out of which 7180 are expected to die. Traditional methods like surgery, radiation therapy, and chemotherapy are not effective in the treatment of metastatic and advanced melanoma. Recent approaches to treat melanoma have focused on biomarkers that play significant roles in cell growth, proliferation, migration, and survival. Several FDA-approved molecular targeted therapies such as tyrosine kinase inhibitors (TKIs) have been developed against genetic biomarkers whose overexpression is implicated in tumorigenesis. The use of targeted therapies as an alternative or supplement to immunotherapy has revolutionized the management of metastatic melanoma. Although this treatment strategy is more efficacious and less toxic in comparison to traditional therapies, targeted therapies are less effective after prolonged treatment due to acquired resistance caused by mutations and activation of alternative mechanisms in melanoma tumors. Recent studies focus on understanding the mechanisms of acquired resistance to these current therapies. Further research is needed for the development of better approaches to improve prognosis in melanoma patients. In this article, various melanoma biomarkers including BRAF, MEK, RAS, c-KIT, VEGFR, c-MET and PI3K are described, and their potential mechanisms for drug resistance are discussed.
Collapse
|
|
14
|
Huang YJ, Gao Y, Wang CJ, Han DX, Zheng Y, Wang WH, Jiang H, Yuan B, Zhang JB. Hydroxyurea regulates the development and survival of B16 Melanoma Cells by upregulating MiR-7013-3p. Int J Med Sci 2021; 18:1877-1885. [PMID: 33746605 PMCID: PMC7976580 DOI: 10.7150/ijms.52177] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 12/18/2020] [Indexed: 12/31/2022] Open
Abstract
miRNAs are a family of short, noncoding RNAs that are involved in many processes in melanoma cells. MITF acts as a master regulator of melanocyte function, development and survival by modulating various genes. Hydroxyurea (HU) is used to treat melanoma, and miRNA expression is altered after HU treatment in B16 melanoma cells. In this study, we screened for miRNAs that were upregulated after HU treatment and that targeted the MITF gene. We found that miR-7013-3p exhibited increased expression after HU treatment and could bind to MITF. miR-7013-3p inhibited melanin production, proliferation, and migration and promoted apoptosis in B16 melanoma cells. The results may provide more information on the roles of miR-7013-3p in B16 melanoma cells.
Collapse
Affiliation(s)
- Yi-Jie Huang
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Yan Gao
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Chang-Jiang Wang
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Dong-Xu Han
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Yi Zheng
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Wen-Hua Wang
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Hao Jiang
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Bao Yuan
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| | - Jia-Bao Zhang
- Department of Laboratory Animals, Jilin Provincial Key Laboratory of Animal Model, Jilin University, Changchun 130062, Jilin, P.R. China
| |
Collapse
|
|
15
|
Kattan WE, Hancock JF. RAS Function in cancer cells: translating membrane biology and biochemistry into new therapeutics. Biochem J 2020; 477:2893-2919. [PMID: 32797215 PMCID: PMC7891675 DOI: 10.1042/bcj20190839] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 07/20/2020] [Accepted: 07/22/2020] [Indexed: 02/07/2023]
Abstract
The three human RAS proteins are mutated and constitutively activated in ∼20% of cancers leading to cell growth and proliferation. For the past three decades, many attempts have been made to inhibit these proteins with little success. Recently; however, multiple methods have emerged to inhibit KRAS, the most prevalently mutated isoform. These methods and the underlying biology will be discussed in this review with a special focus on KRAS-plasma membrane interactions.
Collapse
Affiliation(s)
- Walaa E. Kattan
- Department of Integrative Biology and Pharmacology, McGovern Medical School University of Texas Health Science Center at Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, TX 77030, USA
| | - John F. Hancock
- Department of Integrative Biology and Pharmacology, McGovern Medical School University of Texas Health Science Center at Houston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, TX 77030, USA
| |
Collapse
|
|
16
|
Malik R, Mambetsariev I, Fricke J, Chawla N, Nam A, Pharaon R, Salgia R. MET receptor in oncology: From biomarker to therapeutic target. Adv Cancer Res 2020; 147:259-301. [PMID: 32593403 DOI: 10.1016/bs.acr.2020.04.006] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
First discovered in the 1984, the MET receptor tyrosine kinase (RTK) and its ligand hepatocyte growth factor or HGF (also known as scatter factor or SF) are implicated as key players in tumor cell migration, proliferation, and invasion in a variety of cancers. This pathway also plays a key role during embryogenesis in the development of muscular and nervous structures. High expression of the MET receptor has been shown to correlate with poor prognosis and resistance to therapy. MET exon 14 splicing variants, initially identified by us in lung cancer, is actionable through various tyrosine kinase inhibitors (TKIs). For this reason, this pathway is of interest as a therapeutic target. In this chapter we will be discussing the history of MET, the genetics of this RTK, and give some background on the receptor biology. Furthermore, we will discuss directed therapeutics, mechanisms of resistance, and the future of MET as a therapeutic target.
Collapse
Affiliation(s)
- Raeva Malik
- George Washington University Hospital, Washington, DC, United States
| | - Isa Mambetsariev
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Jeremy Fricke
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Neal Chawla
- Department of Medicine, Advocate Illinois Masonic Medical Center, Chicago, IL, United States
| | - Arin Nam
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Rebecca Pharaon
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States
| | - Ravi Salgia
- Department of Medical Oncology and Therapeutics Research, City of Hope National Medical Center, Duarte, CA, United States.
| |
Collapse
|
|
17
|
Sivakumar M, Jayakumar M, Seedevi P, Sivasankar P, Ravikumar M, Surendar S, Murugan T, Siddiqui SS, Loganathan S. Meta-analysis of functional expression and mutational analysis of c-Met in various cancers. Curr Probl Cancer 2019; 44:100515. [PMID: 31806240 DOI: 10.1016/j.currproblcancer.2019.100515] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 08/29/2019] [Accepted: 10/10/2019] [Indexed: 12/27/2022]
Abstract
Comprehensive genomic profiling is expected to revolutionize cancer therapy. c-Met signaling is responsible for tumorigenesis in various cancers. In this prospective, we present the prevalence of c-Met mutations and copy number alterations across various solid tumors. We used major databases like cBioportal, PubMed, and COSMIC for c-Met mutation and amplification data collection from various cancers. Our result shows complete details about c-Met mutation and its clinical data of various cancers. Hotspot mutation of human c-Met protein reveals that repeatedly and most mutated regions and these hotspots may be a diagnostic tool for cancer confirmation. Amino acid and nucleotide changes and their prevalence were reported in a number of individual cancers. However, we collectively present the amino acid and nucleotide changes in various cancers in this review. Our collection of data for c-Met mutation and its distribution in different cancer tissue is showing that the missense mutation is the major one in all type of cancers. Copy number variation data showing amplification and deletion of human c-Met from various tumor types, lung and central nervous system tumors showing high amplification comparatively other types.
Collapse
Affiliation(s)
- Murugesan Sivakumar
- Department of Environmental Science, Periyar University, Salem, Tamil Nadu, India
| | - Murugesan Jayakumar
- Department of Biochemistry and Biotechnology, Faculty of Science, Annamalai University, Annamalainagar, Tamil Nadu, India
| | - Palaniappan Seedevi
- Department of Environmental Science, Periyar University, Salem, Tamil Nadu, India
| | | | - Muthu Ravikumar
- Department of Environmental Science, Periyar University, Salem, Tamil Nadu, India
| | | | - Tamilselvi Murugan
- Department of Zoology, Government Arts College (Autonomous), Coimbatore, Tamil Nadu, India
| | - Shahid S Siddiqui
- Department of Medicine, University of Chicago, Chicago, IL; Department of Basic and Clinical Oral Sciences, Faculty of Dentistry, Umm Al Qura University, Makkah, Saudi Arabia; Department of Medical Genetics, Faculty of Medicine, Umm Al Qura University, Makkah, Saudi Arabia
| | - Sivakumar Loganathan
- Department of Environmental Science, Periyar University, Salem, Tamil Nadu, India; Department of Medicine, University of Chicago, Chicago, IL.
| |
Collapse
|
|
18
|
Zhou Y, Song KY, Giubellino A. The Role of MET in Melanoma and Melanocytic Lesions. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:2138-2148. [PMID: 31476283 DOI: 10.1016/j.ajpath.2019.08.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 07/28/2019] [Accepted: 08/15/2019] [Indexed: 01/03/2023]
Abstract
Melanoma is the leading cause of death due to cutaneous malignancy and its incidence is on the rise. Several signaling pathways, including receptor tyrosine kinases, have been recognized to have an etiopathogenetic role in the development and progression of precursor melanocytic lesions and malignant melanoma. Among those, the hepatocyte growth factor/MET (HGF/MET) axis is emerging as a critical player not only in the tumor itself but also in the immune microenvironment in which the tumor grows and advances in its development. Moreover, the activation of this pathway has emerged as a paradigm of tumor resistance to modern targeted therapies, and the assessment of its expression in patients' samples may be a valuable biomarker of tumor progression and response to targeted therapy. Here we summarize our current understanding of this important receptor tyrosine kinase in normal melanocyte proliferation/motility, in tumor progression and metastasis, its genetic alterations in certain subtype of melanocytic lesions, and how its pathway has been explored for the development of selective inhibitors.
Collapse
Affiliation(s)
- Yan Zhou
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
| | - Kyu Young Song
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Alessio Giubellino
- Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota; Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota.
| |
Collapse
|
|
19
|
Pietraszek-Gremplewicz K, Simiczyjew A, Dratkiewicz E, Podgórska M, Styczeń I, Matkowski R, Ziętek M, Nowak D. Expression level of EGFR and MET receptors regulates invasiveness of melanoma cells. J Cell Mol Med 2019; 23:8453-8463. [PMID: 31638339 PMCID: PMC6850915 DOI: 10.1111/jcmm.14730] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/13/2019] [Accepted: 09/14/2019] [Indexed: 12/19/2022] Open
Abstract
Epidermal and hepatocyte growth factors can stimulate invasive abilities of melanoma cells, while treatment with combination of their receptors' (EGFR and MET, respectively) inhibitors reduces viability of these cells, as we have previously shown. Proposed therapy has potential; however, used drugs block more than one goal effectively, what raises the question about the real target of analysed inhibitors. For this reason, we analysed direct involvement of these receptors in the invasion of melanoma cells inducing EGFR and MET up‐ and down‐regulations in examined cells. Results were acquired with assays evaluating cell migration and invasion (scratch wound assay, Transwell filter‐based method and single‐cell tracking). We revealed that cells' motile abilities are increased after EGFR overexpression and decreased following EGFR and MET silencing. This outcome correlates with elevated (EGFR up‐regulation) or reduced (EGFR/MET down‐regulation) number of formed invadopodia, visualized with immunofluorescence, and their rate of proteolytic abilities, evaluated by fluorescent gelatin degradation assay, and gelatin zymography, compared to control cells. Above‐mentioned data indicate that both—EGFR and MET signalling is directly connected with melanoma cells invasion, what establishes these receptors as promising targets for anti‐cancer treatment.
Collapse
Affiliation(s)
| | - Aleksandra Simiczyjew
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Ewelina Dratkiewicz
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Marta Podgórska
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Ilona Styczeń
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Rafał Matkowski
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Wroclaw, Poland.,Lower Silesian Oncology Center, Wroclaw, Poland
| | - Marcin Ziętek
- Department of Oncology and Division of Surgical Oncology, Wroclaw Medical University, Wroclaw, Poland.,Lower Silesian Oncology Center, Wroclaw, Poland
| | - Dorota Nowak
- Department of Cell Pathology, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| |
Collapse
|
|
20
|
Muñoz R, Hileeto D, Cruz-Muñoz W, Wood GA, Xu P, Man S, Viloria-Petit A, Kerbel RS. Suppressive impact of metronomic chemotherapy using UFT and/or cyclophosphamide on mediators of breast cancer dissemination and invasion. PLoS One 2019; 14:e0222580. [PMID: 31536574 PMCID: PMC6752870 DOI: 10.1371/journal.pone.0222580] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Accepted: 09/03/2019] [Indexed: 12/17/2022] Open
Abstract
Metronomic chemotherapy using the 5-FU prodrug uracil-tegafur (UFT) and cyclophosphamide (CTX) was previously shown to only modestly delay primary tumor growth, but nevertheless markedly suppressed the development of micro-metastasis in an orthotopic breast cancer xenograft model, using the metastatic variant of the MDA-MB-231 cell line, 231/LM2-4. Furthermore, a remarkable prolongation of survival, with no toxicity, was observed in a model of postsurgical advanced metastatic disease. A question that has remained unanswered is the seemingly selective anti-metastatic mechanisms of action responsible for this treatment. We assessed the in vivo effect of metronomic UFT, CTX or their combination, on vascular density, collagen deposition and c-Met (cell mediators or modulators of tumor cell invasion or dissemination) via histochemistry/immunohistochemistry of primary tumor sections. We also assessed the effect of continuous exposure to low and non-toxic doses of active drug metabolites 5-fluorouracil (5-FU), 4-hydroperoxycyclophosphamide (4-HC) or their combination, on 231/LM2-4 cell invasiveness in vitro. In the in vivo studies, a significant reduction in vascular density and p-Met[Y1003] levels was associated with UFT+CTX treatment. All treatments reduced intratumoral collagen deposition. In the in vitro studies, a significant reduction of collagen IV invasion by all treatments was observed. The 3D structures formed by 231/LM2-4 on Matrigel showed a predominantly Mass phenotype under treated conditions and Stellate phenotype in untreated cultures. Taken together, the results suggest the low-dose metronomic chemotherapy regimens tested can suppress several mediators of tumor invasiveness highlighting a new perspective for the anti-metastatic efficacy of metronomic chemotherapy.
Collapse
Affiliation(s)
- Raquel Muñoz
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
| | - Denise Hileeto
- School of Optometry & Vision Science, University of Waterloo, Waterloo, Ontario, Canada
| | - William Cruz-Muñoz
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
| | - Geoffrey A. Wood
- Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Ping Xu
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
| | - Shan Man
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
| | - Alicia Viloria-Petit
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada
| | - Robert S. Kerbel
- Biological Sciences Platform, Sunnybrook Research Institute, Toronto, Canada
- Department of Medical Biophysics, University of Toronto, Toronto, Canada
| |
Collapse
|
|
21
|
Heenatigala Palliyage G, Singh S, Ashby CR, Tiwari AK, Chauhan H. Pharmaceutical Topical Delivery of Poorly Soluble Polyphenols: Potential Role in Prevention and Treatment of Melanoma. AAPS PharmSciTech 2019; 20:250. [PMID: 31297635 DOI: 10.1208/s12249-019-1457-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 06/06/2019] [Indexed: 01/10/2023] Open
Abstract
Melanoma is regarded as the fifth and sixth most common cancer in men and women, respectively, and it is estimated that one person dies from melanoma every hour in the USA. Unfortunately, the treatment of melanoma is difficult because of its aggressive metastasis and resistance to treatment. The treatment of melanoma continues to be a challenging issue due to the limitations of available treatments such as a low response rate, severe adverse reactions, and significant toxicity. Natural polyphenols have attracted considerable attention from the scientific community due to their chemopreventive and chemotherapeutic efficacy. It has been suggested that poorly soluble polyphenols such as curcumin, resveratrol, quercetin, coumarin, and epigallocatechin-3-gallate may have significant benefits in the treatment of melanoma due to their antioxidant, anti-inflammatory, antiproliferative, and chemoprotective efficacies. The major obstacles for the use of polyphenolic compounds are low stability and poor bioavailability. Numerous nanoformulations, including solid lipid nanoparticles, polymeric nanoparticles, micelles, and liposomes, have been formulated to enhance the bioavailability and stability, as well as the therapeutic efficacy of polyphenols. This review will provide an overview of poorly soluble polyphenols that have been reported to have antimetastatic efficacy in melanomas.
Collapse
|
|
22
|
Cold atmospheric plasma and silymarin nanoemulsion synergistically inhibits human melanoma tumorigenesis via targeting HGF/c-MET downstream pathway. Cell Commun Signal 2019; 17:52. [PMID: 31126298 PMCID: PMC6534917 DOI: 10.1186/s12964-019-0360-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2019] [Accepted: 05/01/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Recent studies claimed the important role of cold atmospheric plasma (CAP) with nanotechnology in cancer treatments. In this study, silymarin nanoemulsion (SN) was used along with air CAP as therapeutic agent to counter human melanoma. METHODS In this study, we examined the combined treatment of CAP and SN on G-361 human melanoma cells by evaluating cellular toxicity levels, reactive oxygen and nitrogen species (RONS) levels, DNA damage, melanoma-specific markers, apoptosis, caspases and poly ADP-ribose polymerase-1 (PARP-1) levels using flow cytometer. Dual-treatment effects on the epithelial-mesenchymal transition (EMT), Hepatocyte growth factor (HGF/c-MET) pathway, sphere formation and the reversal of EMT were also assessed using western blotting and microscopy respectively. SN and plasma-activated medium (PAM) were applied on tumor growth and body weight and melanoma-specific markers and the mesenchymal markers in the tumor xenograft nude mice model were checked. RESULTS Co-treatment of SN and air CAP increased the cellular toxicity in a time-dependent manner and shows maximum toxicity at 200 nM in 24 h. Intracellular RONS showed significant generation of ROS (< 3 times) and RNS (< 2.5 times) in dual-treated samples compared to control. DNA damage studies were assessed by estimating the level of γ-H2AX (1.8 times), PD-1 (> 2 times) and DNMT and showed damage in G-361 cells. Increase in Caspase 8,9,3/7 (> 1.5 times), PARP level (2.5 times) and apoptotic genes level were also observed in dual treated group and hence blocking HGF/c-MET pathway. Decrease in EMT markers (E-cadherin, YKL-40, N-cadherin, SNAI1) were seen with simultaneously decline in melanoma cells (BRAF, NAMPT) and stem cells (CD133, ABCB5) markers. In vivo results showed significant reduction in SN with PAM with reduction in tumor weight and size. CONCLUSIONS The use of air CAP using μ-DBD and the SN can minimize the malignancy effects of melanoma cells by describing HGF/c-MET molecular mechanism of acting on G-361 human melanoma cells and in mice xenografts, possibly leading to suitable targets for innovative anti-melanoma approaches in the future.
Collapse
|
|
23
|
Kumar SR, Gajagowni S, Bryan JN, Bodenhausen HM. Molecular targets for tivantinib (ARQ 197) and vasculogenic mimicry in human melanoma cells. Eur J Pharmacol 2019; 853:316-324. [PMID: 30954563 DOI: 10.1016/j.ejphar.2019.04.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2019] [Revised: 03/27/2019] [Accepted: 04/02/2019] [Indexed: 11/25/2022]
Abstract
Tivantinib (TivB) was reported previously to target MET and microtubule assembly in different cells resulting in cytotoxicity. However, its other cellular targets remain unknown, especially the proteins involved in focal adhesion and cytoskeletal organization. We studied the effect of TivB on vinculin a focal adhesion protein, and RhoC, a GTPase which promote the reorganization of cytoskeleton. Biomolecules involved in vasculogenic mimicry (VM) previously not reported in melanoma, and their susceptibility to TivB was also evaluated. TivB affects the viability and apoptosis of human melanoma cells depending on the cell type. Vinculin and RhoC were increased in the presence of TivB and affected the integrity of actin filaments and altered the cellular morphology. TivB disrupts the VM exhibited by melanoma cells in 3D matrix. Roundabout Guidance Receptor 4 (Robo4), a receptor protein implicated in axonal guidance and angiogenesis and its ligand Slit2 are expressed in human C8161 and WM793 melanoma cells, but absent in other melanoma cells including normal melanocytes. VM is more prominent in C8161 cells and could be blocked by siRNA mediated silencing of Robo4 mRNA, but TivB does not affect Robo4 in C8161 cells. Immunoblot analysis indicated no changes in Robo4 and Slit2 protein expression, however, both vinculin and RhoC protein increased in TivB treated melanoma cells. These results suggest that TivB affects cell cytoskeleton and morphology by altering proteins such as vinculin and RhoC. Our studies indicate TivB could target molecules other than MET in melanoma cells, which may provide insight into its alternate mechanism of action.
Collapse
Affiliation(s)
- Senthil R Kumar
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA; Department of Surgery, Ellis Fischel Cancer Centre, School of Medicine, University of Missouri, Columbia, MO, 65201, USA; Harry S. Truman Veterans Medical Center, Columbia, MO, 65201, USA.
| | - Saivaroon Gajagowni
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
| | - Jeffrey N Bryan
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
| | - Hannah M Bodenhausen
- Comparative Oncology, Radiobiology and Epigenetics Laboratory, College of Veterinary Medicine, University of Missouri, Columbia, MO, 65211, USA
| |
Collapse
|
|
24
|
Orlando E, Aebersold DM, Medová M, Zimmer Y. Oncogene addiction as a foundation of targeted cancer therapy: The paradigm of the MET receptor tyrosine kinase. Cancer Lett 2019; 443:189-202. [DOI: 10.1016/j.canlet.2018.12.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 11/20/2018] [Accepted: 12/03/2018] [Indexed: 12/13/2022]
|
|
25
|
HGF/c-MET Signaling in Melanocytes and Melanoma. Int J Mol Sci 2018; 19:ijms19123844. [PMID: 30513872 PMCID: PMC6321285 DOI: 10.3390/ijms19123844] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 11/26/2018] [Accepted: 11/30/2018] [Indexed: 12/17/2022] Open
Abstract
Hepatocyte growth factor (HGF)/ mesenchymal-epithelial transition factor (c-MET) signaling is involved in complex cellular programs that are important for embryonic development and tissue regeneration, but its activity is also utilized by cancer cells during tumor progression. HGF and c-MET usually mediate heterotypic cell–cell interactions, such as epithelial–mesenchymal, including tumor–stroma interactions. In the skin, dermal fibroblasts are the main source of HGF. The presence of c-MET on keratinocytes is crucial for wound healing in the skin. HGF is not released by normal melanocytes, but as melanocytes express c-MET, they are receptive to HGF, which protects them from apoptosis and stimulates their proliferation and motility. Dissimilar to melanocytes, melanoma cells not only express c-MET, but also release HGF, thus activating c-MET in an autocrine manner. Stimulation of the HGF/c-MET pathways contributes to several processes that are crucial for melanoma development, such as proliferation, survival, motility, and invasiveness, including distant metastatic niche formation. HGF might be a factor in the innate and acquired resistance of melanoma to oncoprotein-targeted drugs. It is not entirely clear whether elevated serum HGF level is associated with low progression-free survival and overall survival after treatment with targeted therapies. This review focuses on the role of HGF/c-MET signaling in melanoma with some introductory information on its function in skin and melanocytes.
Collapse
|
|
26
|
MiR-140-5p suppresses retinoblastoma cell growth via inhibiting c-Met/AKT/mTOR pathway. Biosci Rep 2018; 38:BSR20180776. [PMID: 30291212 PMCID: PMC6265618 DOI: 10.1042/bsr20180776] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Revised: 08/18/2018] [Accepted: 08/22/2018] [Indexed: 12/16/2022] Open
Abstract
MiR-140-5p is low expression and acts as a tumor suppressor in various types of human cancers. However, the potential role of miR-140-5p in retinoblastoma (RB) remains unknown. In the present study, we performed the miRNA microarray analysis to investigate whether miRNAs expression are associated with RB tumorigenesis in RB tissues. We found that a large set of miRNAs were ectopic expressions and miR-140-5p is most significantly down-regulated in human RB tissues compared with normal retinas. In addition, low miR-140-5p expression is associated with clinicopathological features (differentiation, invasion, T classification, N classification, cTNM stage, and largest tumor base) and poor survival in RB patients. Furthermore, our results showed that overexpression of miR-140-5p suppresses proliferation and induces apoptosis and cell cycle arrest in RB cell. Meanwhile, we confirmed that c-Met is the functional target of miR-140-5p in RB cell, and miR-140-5p expression is negatively correlated with c-Met in RB tissues. We also found that inhibition of c-Met also suppresses proliferation and induces apoptosis and cell cycle arrest in RB cell. Interestingly, c-Met can rescue the suppressive effects of miR-140-5p on RB cell growth and cell cycle arrest. More importantly, our findings indicated that miR-140-5p may inhibit cell growth via blocking c-Met/AKT/mTOR signaling pathway. Collectively, these results suggested that miR-140-5p might be a potential biomarker and target in the diagnosis and treatment of RB.
Collapse
|
|
27
|
Li W, Zheng H, Xu J, Cao S, Xu X, Xiao P. Imaging c-Met expression using 18F-labeled binding peptide in human cancer xenografts. PLoS One 2018; 13:e0199024. [PMID: 29894497 PMCID: PMC5997322 DOI: 10.1371/journal.pone.0199024] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 05/30/2018] [Indexed: 11/18/2022] Open
Abstract
Objectives c-Met is a receptor tyrosine kinase shown inappropriate expression and actively involved in progression and metastasis in most types of human cancer. Development of c-Met-targeted imaging and therapeutic agents would be extremely useful. Previous studies reported that c-Met-binding peptide (Met-pep1, YLFSVHWPPLKA) specifically targets c-Met receptor. Here, we evaluated 18F-labeled Met-pep1 for PET imaging of c-Met positive tumor in human head and neck squamous cell carcinoma (HNSCC) xenografted mice. Methods c-Met-binding peptide, Met-pep1, was synthesized and labeled with 4-nitrophenyl [18F]-2-fluoropropionate ([18F]-NPFP) ([18F]FP-Met-pep1). The cell uptake, internalization and efflux of [18F]FP-Met-pep1 were assessed in UM-SCC-22B cells. In vivo pharmacokinetics, blocking and biodistribution of the radiotracers were investigated in tumor-bearing nude mice by microPET imaging. Results The radiolabeling yield for [18F]FP-Met-pep1 was over 55% with 97% purity. [18F]FP-Met-pep1 showed high tumor uptake in UM-SCC-22B tumor-bearing mice with clear visualization. The specificity of the imaging tracer was confirmed by significantly decreased tumor uptake after co-administration of unlabeled Met-pep1 peptides. Prominent uptake and rapid excretion of [18F]FP-Met-pep1 was also observed in the kidney, suggesting this tracer is mainly excreted through the renal-urinary routes. Ex vivo biodistribution showed similar results that were consistent with microPET imaging data. Conclusions These results suggest that 18F-labeled c-Met peptide may potentially be used for imaging c-Met positive HNSCC cancer in vivo and for c-Met-targeted cancer therapy.
Collapse
Affiliation(s)
- Weihua Li
- Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
- * E-mail: (WHL); (PX)
| | - Hongqun Zheng
- Department of Surgical Oncology and Hepatobiliary Surgery, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Jiankai Xu
- College of Bioinformatics Science and Technology, Harbin Medical University, Harbin, China
| | - Shaodong Cao
- Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Xiuan Xu
- Department of Medical Imaging and Nuclear Medicine, the Fourth Affiliated Hospital, Harbin Medical University, Harbin, China
| | - Peng Xiao
- New Iberia Research Center, University of Louisiana at Lafayette, New Iberia, Louisiana, United States of America
- * E-mail: (WHL); (PX)
| |
Collapse
|
|
28
|
Linklater ES, Tovar EA, Essenburg CJ, Turner L, Madaj Z, Winn ME, Melnik MK, Korkaya H, Maroun CR, Christensen JG, Steensma MR, Boerner JL, Graveel CR. Targeting MET and EGFR crosstalk signaling in triple-negative breast cancers. Oncotarget 2018; 7:69903-69915. [PMID: 27655711 PMCID: PMC5342523 DOI: 10.18632/oncotarget.12065] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/01/2016] [Indexed: 12/14/2022] Open
Abstract
There is a vital need for improved therapeutic strategies that are effective in both primary and metastatic triple-negative breast cancer (TNBC). Current treatment options for TNBC patients are restricted to chemotherapy; however tyrosine kinases are promising druggable targets due to their high expression in multiple TNBC subtypes. Since coexpression of receptor tyrosine kinases (RTKs) can promote signaling crosstalk and cell survival in the presence of kinase inhibitors, it is likely that multiple RTKs will need to be inhibited to enhance therapeutic benefit and prevent resistance. The MET and EGFR receptors are actionable targets due to their high expression in TNBC; however crosstalk between MET and EGFR has been implicated in therapeutic resistance to single agent use of MET or EGFR inhibitors in several cancer types. Therefore it is likely that dual inhibition of MET and EGFR is required to prevent crosstalk signaling and acquired resistance. In this study, we evaluated the heterogeneity of MET and EGFR expression and activation in primary and metastatic TNBC tumorgrafts and determined the efficacy of MET (MGCD265 or crizotinib) and/or EGFR (erlotinib) inhibition against TNBC progression. Here we demonstrate that combined MET and EGFR inhibition with either MGCD265 and erlotinib treatment or crizotinib and erlotinib treatment were highly effective at abrogating tumor growth and significantly decreased the variability in treatment response compared to monotherapy. These results advance our understanding of the RTK signaling architecture in TNBC and demonstrate that combined MET and EGFR inhibition may be a promising therapeutic strategy for TNBC patients.
Collapse
Affiliation(s)
- Erik S Linklater
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Elizabeth A Tovar
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Curt J Essenburg
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Lisa Turner
- Pathology and Biorepository Core, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Zachary Madaj
- Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Mary E Winn
- Bioinformatics and Biostatistics Core, Van Andel Research Institute, Grand Rapids, Michigan, USA
| | - Marianne K Melnik
- Spectrum Health Cancer Center, Spectrum Health System, Grand Rapids, Michigan, USA.,Grand Rapids Medical Education Partners, General Surgery Residency Program, Grand Rapids, Michigan, USA.,Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA
| | - Hasan Korkaya
- Molecular Oncology and Biomarkers Program, Augusta University, Augusta, Georgia, USA
| | - Christiane R Maroun
- Mirati Therapeutics, San Diego, California, USA.,Current address: Vertex Pharmaceuticals (Canada) Inc., Laval, Quebec, Canada
| | | | - Matthew R Steensma
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA.,Spectrum Health Cancer Center, Spectrum Health System, Grand Rapids, Michigan, USA.,Department of Surgery, Michigan State University College of Human Medicine, Grand Rapids, Michigan, USA
| | - Julie L Boerner
- Biobanking and Correlative Sciences Core, Karmanos Cancer Institute, Detroit, Michigan, USA
| | - Carrie R Graveel
- Center for Cancer and Cell Biology, Van Andel Research Institute, Grand Rapids, Michigan, USA
| |
Collapse
|
|
29
|
Demkova L, Kucerova L. Role of the HGF/c-MET tyrosine kinase inhibitors in metastasic melanoma. Mol Cancer 2018; 17:26. [PMID: 29455657 PMCID: PMC5817811 DOI: 10.1186/s12943-018-0795-z] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 02/01/2018] [Indexed: 02/08/2023] Open
Abstract
Metastatic disease in a cancer patient still remains a therapeutic challenge. Metastatic process involves many steps, during which malignant cells succeed to activate cellular pathways promoting survival in hostile environment, engraftment and growth at the distant site from the primary tumor. Melanoma is known for its high propensity to produce metastases even at the early stages of the disease. Here we summarize the most important molecular mechanisms which were associated with the melanoma metastasis. Then, we specifically focus on the signaling pathway mediated by hepatocyte growth factor (HGF) and its receptor c-Met, which play an important role during physiological processes and were been associated with tumorigenesis. We also focus on the effect of the small molecule inhibitors of the tyrosine kinase domain of the c-Met receptor and its effects on properties of melanoma cell. We summarize recent studies, which involved inhibition of the HGF/c-Met signaling in order to decrease melanoma growth and metastatic capacity.
Collapse
Affiliation(s)
- Lucia Demkova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia
| | - Lucia Kucerova
- Laboratory of Molecular Oncology, Cancer Research Institute, Biomedical Research Center of the Slovak Academy of Sciences, Dubravska cesta 9, 845 05, Bratislava, Slovakia.
| |
Collapse
|
|
30
|
Chhabra G, Wojdyla L, Frakes M, Schrank Z, Leviskas B, Ivancich M, Vinay P, Ganapathy R, Ramirez BE, Puri N. Mechanism of Action of G-Quadruplex-Forming Oligonucleotide Homologous to the Telomere Overhang in Melanoma. J Invest Dermatol 2017; 138:903-910. [PMID: 29203363 DOI: 10.1016/j.jid.2017.11.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2016] [Revised: 11/09/2017] [Accepted: 11/13/2017] [Indexed: 12/19/2022]
Abstract
T-oligo, a guanine-rich oligonucleotide homologous to the 3'-telomeric overhang of telomeres, elicits potent DNA-damage responses in melanoma cells; however, its mechanism of action is largely unknown. Guanine-rich oligonucleotides can form G-quadruplexes (G4), which are stabilized by the hydrogen bonding of guanine residues. In this study, we confirmed the G4-forming capabilities of T-oligo using nondenaturing PAGE, nuclear magnetic resonance, and immunofluorescence. Using an anti-G-quadruplex antibody, we showed that T-oligo can form G4 in the nuclei of melanoma cells. Furthermore, using DNase I in a nuclease degradation assay, G4-T-oligo was found to be more stable than single-stranded T-oligo. G4-T-oligo had decreased antiproliferative effects compared with single-stranded T-oligo. However, G4-T-oligo has similar cellular uptake as single-stranded T-oligo, as shown by FACS analysis. Inhibition of JNK, which causes DNA damage-induced apoptosis, partially reversed the antiproliferative activity of T-oligo. T-oligo also inhibited mRNA expression of human telomerase reverse transcriptase, a catalytic subunit of telomerase that was reversed by JNK inhibition. Furthermore, two shelterin complex proteins TRF2/POT1 were found to be up-regulated and bound by T-oligo, suggesting that T-oligo may mediate dissociation of these proteins from the telomere overhang. These studies show that T-oligo can form a G-quadruplex and that the antitumor effects of T-oligo may be mediated through POT1/TRF2 and via human telomerase reverse transcriptase inhibition through JNK activation.
Collapse
Affiliation(s)
- Gagan Chhabra
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | - Luke Wojdyla
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | - Mark Frakes
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | - Zachary Schrank
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | - Brandon Leviskas
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | - Marko Ivancich
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | - Pooja Vinay
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA
| | | | - Benjamin E Ramirez
- Center for Structural Biology, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Neelu Puri
- University of Illinois College of Medicine at Rockford, Rockford, Illinois, USA.
| |
Collapse
|
|
31
|
Robinson JP, Rebecca VW, Kircher DA, Silvis MR, Smalley I, Gibney GT, Lastwika KJ, Chen G, Davies MA, Grossman D, Smalley KS, Holmen SL, VanBrocklin MW. Resistance mechanisms to genetic suppression of mutant NRAS in melanoma. Melanoma Res 2017; 27:545-557. [PMID: 29076949 PMCID: PMC5683096 DOI: 10.1097/cmr.0000000000000403] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Targeted therapies have revolutionized cancer care, but the development of resistance remains a challenge in the clinic. To identify rational targets for combination strategies, we used an established melanoma mouse model and selected for resistant tumors following genetic suppression of NRAS expression. Complete tumor regression was observed in all mice, but 40% of tumors recurred. Analysis of resistant tumors showed that the most common mechanism of resistance was overexpression and activation of receptor tyrosine kinases (RTKs). Interestingly, the most commonly overexpressed RTK was Met and inhibition of Met overcame NRAS resistance in this context. Analysis of NRAS mutant human melanoma cells showed enhanced efficacy of cytotoxicity with combined RTK and mitogen-activated protein kinase kinase inhibition. In this study, we establish the importance of adaptive RTK signaling in the escape of NRAS mutant melanoma from inhibition of RAS and provide the rationale for combined blockade of RAS and RTK signaling in this context.
Collapse
Affiliation(s)
| | - Vito W. Rebecca
- Department of Medicine and Abramson Cancer Center; University of Pennsylvania School of Medicine, Philadelphia, PA USA
| | - David A. Kircher
- Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | - Mark R. Silvis
- Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | - Inna Smalley
- Tumor Biology, Moffitt Cancer Center, Tampa, Florida, USA
- Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Geoffrey T. Gibney
- Lombardi Comprehensive Cancer Center, MedStar Georgetown University Hospital, Washington DC, USA
| | - Kristin J. Lastwika
- Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
| | - Guo Chen
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Michael A. Davies
- Department of Melanoma Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Douglas Grossman
- Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Department of Dermatology, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | - Keiran S.M. Smalley
- Tumor Biology, Moffitt Cancer Center, Tampa, Florida, USA
- Cutaneous Oncology, Moffitt Cancer Center, Tampa, Florida, USA
| | - Sheri L. Holmen
- Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| | - Matthew W. VanBrocklin
- Department of Oncological Sciences, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Department of Surgery, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
- Huntsman Cancer Institute, University of Utah Health Sciences Center, Salt Lake City, Utah, USA
| |
Collapse
|
|
32
|
MET receptor variant R970C favors calpain-dependent generation of a fragment promoting epithelial cell scattering. Oncotarget 2017; 8:11268-11283. [PMID: 28061464 PMCID: PMC5355264 DOI: 10.18632/oncotarget.14499] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 12/26/2016] [Indexed: 12/20/2022] Open
Abstract
The receptor tyrosine kinase MET and its ligand, the hepatocyte growth factor, are essential to embryonic development, whereas deregulation of MET signaling is associated with tumorigenesis leading to various cancers, including lung carcinoma. Mutations in the MET kinase domain lead to constitutive kinase activity and are associated with tumorigenesis. In lung cancer, however, some mutations are found in the juxtamembrane domain, and their functional consequences are unknown. Because the juxtamembrane domain of MET is targeted by several proteolytic cleavages, involved in its degradation during cell death or under steady-state conditions, we evaluated the influence of these mutations on the MET proteolytic cleavages. In stably transfected epithelial cells expressing MET, the juxtamembrane mutations R970C, P991S, and T992I were found not to modify the known caspase or presenilin-dependent regulated intramembrane proteolysis. Yet when overexpressed, the R970C variant caused generation of an as yet undescribed 45-kDa fragment (p45 MET). This fragment was found in the confluent lung cancer cell line NCI-H1437 carrying the R970C mutation and at a lesser extent in cell lines expressing WT MET, suggesting that R970C mutation favors this cleavage. Generation of p45 MET required the activity of the calpain proteases, confirming the involvement of proteolysis. Ectopic expression of reconstituted p45 MET in epithelial cell lines favored cell scattering and invasion indicating active role of this fragment in HGF/SF induced responses. Hence, although the juxtamembrane mutations of MET do not affect its known proteolytic cleavages, the R970C MET variant favors calpain dependent proteolytic cleavage in lung cancer cells.
Collapse
|
|
33
|
Tang XL, Yan L, Zhu L, Jiao DM, Chen J, Chen QY. Salvianolic acid A reverses cisplatin resistance in lung cancer A549 cells by targeting c-met and attenuating Akt/mTOR pathway. J Pharmacol Sci 2017; 135:1-7. [DOI: 10.1016/j.jphs.2017.06.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 06/26/2017] [Accepted: 06/28/2017] [Indexed: 12/23/2022] Open
|
|
34
|
Yeung CLA, Tsang TY, Yau PL, Kwok TT. Human papillomavirus type 16 E6 suppresses microRNA-23b expression in human cervical cancer cells through DNA methylation of the host gene C9orf3. Oncotarget 2017; 8:12158-12173. [PMID: 28077801 PMCID: PMC5355333 DOI: 10.18632/oncotarget.14555] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 11/21/2016] [Indexed: 11/25/2022] Open
Abstract
Oncogenic protein E6 of human papillomavirus type 16 (HPV-16) is believed to involve in the aberrant methylation in cervical cancer as it upregulates DNA methyltransferase 1 (DNMT1) through tumor suppressor p53. In addition, DNA demethylating agent induces the expression of one of the HPV-16 E6 regulated microRNAs (miRs), miR-23b, in human cervical carcinoma SiHa cells. Thus, the importance of DNA methylation and miR-23b in HPV-16 E6 associated cervical cancer development is investigated. In the present study, however, it is found that miR-23b is not embedded in any typical CpG island. Nevertheless, a functional CpG island is predicted in the promoter region of C9orf3, the host gene of miR-23b, and is validated by methylation-specific PCR and bisulfite genomic sequencing analyses. Besides, c-MET is confirmed to be a target gene of miR-23b. Silencing of HPV-16 E6 is found to increase the expression of miR-23b, decrease the expression of c-MET and thus induce the apoptosis of SiHa cells through the c-MET downstream signaling pathway. Taken together, the tumor suppressive miR-23b is epigenetically inactivated through its host gene C9orf3 and this is probably a critical pathway during HPV-16 E6 associated cervical cancer development.
Collapse
Affiliation(s)
- Chi Lam Au Yeung
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.,Department of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tsun Yee Tsang
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Pak Lun Yau
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Tim Tak Kwok
- School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| |
Collapse
|
|
35
|
Chan XY, Singh A, Osman N, Piva TJ. Role Played by Signalling Pathways in Overcoming BRAF Inhibitor Resistance in Melanoma. Int J Mol Sci 2017; 18:ijms18071527. [PMID: 28708099 PMCID: PMC5536016 DOI: 10.3390/ijms18071527] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2017] [Revised: 07/06/2017] [Accepted: 07/12/2017] [Indexed: 12/15/2022] Open
Abstract
The discovery of the BRAFV600E mutation led to the development of vemurafenib (PLX4032), a selective BRAF inhibitor specific to the kinase, for the treatment of metastatic melanomas. However, initial success of the drug was dampened by the development of acquired resistance. Melanoma was shown to relapse in patients following treatment with vemurafenib which eventually led to patients' deaths. It has been proposed that mechanisms of resistance can be due to (1) reactivation of the mitogen-activated protein kinase (MAPK) signalling pathway via secondary mutations, amplification or activation of target kinase(s), (2) the bypass of oncogenic pathway via activation of alternative signalling pathways, (3) other uncharacterized mechanisms. Studies showed that receptor tyrosine kinases (RTK) such as PDGFRβ, IGF1R, EGFR and c-Met were overexpressed in melanoma cells. Along with increased secretion of growth factors such as HGF and TGF-α, this will trigger intracellular signalling cascades. This review discusses the role MAPK and Phosphatidylinositol-3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathways play in the mechanism of resistance of melanomas.
Collapse
Affiliation(s)
- Xian Yang Chan
- School of Health & Biomedical Sciences, RMIT University, Bundoora 3083, Victoria, Australia.
| | - Alamdeep Singh
- School of Health & Biomedical Sciences, RMIT University, Bundoora 3083, Victoria, Australia.
| | - Narin Osman
- School of Health & Biomedical Sciences, RMIT University, Bundoora 3083, Victoria, Australia.
- Department of Immunology, Monash University, Melbourne 3004, Victoria, Australia.
- Department of Pharmacy, University of Queensland, Woolloongabba 4102, Queensland, Australia.
| | - Terrence J Piva
- School of Health & Biomedical Sciences, RMIT University, Bundoora 3083, Victoria, Australia.
| |
Collapse
|
|
36
|
Wilms C, Kroeger CM, Hainzl AV, Banik I, Bruno C, Krikki I, Farsam V, Wlaschek M, Gatzka MV. MYSM1/2A-DUB is an epigenetic regulator in human melanoma and contributes to tumor cell growth. Oncotarget 2017; 8:67287-67299. [PMID: 28978033 PMCID: PMC5620173 DOI: 10.18632/oncotarget.18617] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2016] [Accepted: 05/31/2017] [Indexed: 01/12/2023] Open
Abstract
Histone modifying enzymes, such as histone deacetylases (HDACs) and polycomb repressive complex (PRC) components, have been implicated in regulating tumor growth, epithelial-mesenchymal transition, tumor stem cell maintenance, or repression of tumor suppressor genes - and may be promising targets for combination therapies of melanoma and other cancers. According to recent findings, the histone H2A deubiquitinase 2A-DUB/Mysm1 interacts with the p53-axis in hematopoiesis and tissue differentiation in mice, in part by modulating DNA-damage responses in stem cell and progenitor compartments. Based on the identification of alterations in skin pigmentation and melanocyte specification in Mysm1-deficient mice, we hypothesized that MYSM1 may be involved in melanoma formation. In human melanoma samples, expression of MYSM1 was increased compared with normal skin melanocytes and nevi and co-localized with melanocyte markers such as Melan-A and c-KIT. Similarly, in melanoma cell lines A375 and SK-MEL-28 and in murine skin, expression of the deubiquitinase was detectable at the mRNA and protein level that was inducible by growth factor signals and UVB exposure, respectively. Upon stable silencing of MYSM1 in A375 and SK-MEL-28 melanoma cells by lentivirally-mediated shRNA expression, survival and proliferation were significantly reduced in five MYSM1 shRNA cell lines analyzed compared with control cells. In addition, MYSM1-silenced melanoma cells proliferated less well in softagar assays. In context with our finding that MYSM1 bound to the c-MET promoter region in close vicinity to PAX3 in melanoma cells, our data indicate that MYSM1 is an epigenetic regulator of melanoma growth and potentially promising new target for tumor therapy.
Collapse
Affiliation(s)
- Christina Wilms
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| | - Carsten M Kroeger
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| | - Adelheid V Hainzl
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| | - Ishani Banik
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany.,ETH, 8092 Zurich, Switzerland
| | - Clara Bruno
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany.,Department of Neurology, Ulm University, 89081 Ulm, Germany
| | - Ioanna Krikki
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| | - Vida Farsam
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| | - Meinhard Wlaschek
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| | - Martina V Gatzka
- Department of Dermatology and Allergic Diseases, Ulm University, 89081 Ulm, Germany
| |
Collapse
|
|
37
|
Daud A, Kluger HM, Kurzrock R, Schimmoller F, Weitzman AL, Samuel TA, Moussa AH, Gordon MS, Shapiro GI. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. Br J Cancer 2017; 116:432-440. [PMID: 28103611 PMCID: PMC5318966 DOI: 10.1038/bjc.2016.419] [Citation(s) in RCA: 57] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Revised: 10/20/2016] [Accepted: 11/14/2016] [Indexed: 01/20/2023] Open
Abstract
BACKGROUND A phase II randomised discontinuation trial assessed cabozantinib (XL184), an orally bioavailable inhibitor of tyrosine kinases including VEGF receptors, MET, and AXL, in a cohort of patients with metastatic melanoma. METHODS Patients received cabozantinib 100 mg daily during a 12-week lead-in. Patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumours (RECIST) at week 12 were randomised to cabozantinib or placebo. Primary endpoints were objective response rate (ORR) at week 12 and postrandomisation progression-free survival (PFS). RESULTS Seventy-seven patients were enroled (62% cutaneous, 30% uveal, and 8% mucosal). At week 12, the ORR was 5%; 39% of patients had SD. During the lead-in phase, reduction in target lesions from baseline was seen in 55% of evaluable patients overall and in 59% of evaluable patients with uveal melanoma. Median PFS after randomisation was 4.1 months with cabozantinib and 2.8 months with placebo (hazard ratio of 0.59; P=0.284). Median PFS from study day 1 was 3.8 months, 6-month PFS was 33%, and median overall survival was 9.4 months. The most common grade 3/4 adverse events were fatigue (14%), hypertension (10%), and abdominal pain (8%). One treatment-related death was reported from peritonitis due to diverticular perforation. CONCLUSIONS Cabozantinib has clinical activity in patients with metastatic melanoma, including uveal melanoma. Further clinical investigation is warranted.
Collapse
Affiliation(s)
- Adil Daud
- University of California, San Francisco Medical Center at Parnassus, 1600 Divisadero Street, MZ Bldg A, San Francisco, CA 94115, USA
| | - Harriet M Kluger
- Yale Cancer Center, Yale University School of Medicine, 333 Cedar Street, PO Box 208028, New Haven, CT 06520-8028, USA
| | - Razelle Kurzrock
- University of California, San Diego Moores Cancer Center, 3855 Health Sciences Drive, MC #0658, La Jolla, CA 92093-0658, USA
| | | | - Aaron L Weitzman
- Exelixis Inc., 210 E. Grand Avenue, South San Francisco, CA 94080, USA
| | - Thomas A Samuel
- Department of Hematology/Oncology, Cleveland Clinic Florida, 2950 Cleveland Clinic Blvd, Weston, FL 33331, USA
| | - Ali H Moussa
- Cancer Care Associates, 1810 E 15th Street, Tulsa, OK 74104, USA
| | - Michael S Gordon
- Pinnacle Oncology Hematology, 9055 E. Del Camino, Suite 100, Scottsdale, AZ 85258, USA
| | - Geoffrey I Shapiro
- Department of Medical Oncology, Dana-Farber Cancer Institute, Early Drug Development Center, 450 Brookline Avenue, Boston, MA 02215, USA
| |
Collapse
|
|
38
|
Zhang RY, Yu ZH, Zeng L, Zhang S, Bai Y, Miao J, Chen L, Xie J, Zhang ZY. SHP2 phosphatase as a novel therapeutic target for melanoma treatment. Oncotarget 2016; 7:73817-73829. [PMID: 27650545 PMCID: PMC5342016 DOI: 10.18632/oncotarget.12074] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2016] [Accepted: 09/02/2016] [Indexed: 12/23/2022] Open
Abstract
Melanoma ranks among the most aggressive and deadly human cancers. Although a number of targeted therapies are available, they are effective only in a subset of patients and the emergence of drug resistance often reduces durable responses. Thus there is an urgent need to identify new therapeutic targets and develop more potent pharmacological agents for melanoma treatment. Herein we report that SHP2 levels are frequently elevated in melanoma, and high SHP2 expression is significantly associated with more metastatic phenotype and poorer prognosis. We show that SHP2 promotes melanoma cell viability, motility, and anchorage-independent growth, through activation of both ERK1/2 and AKT signaling pathways. We demonstrate that SHP2 inhibitor 11a-1 effectively blocks SHP2-mediated ERK1/2 and AKT activation and attenuates melanoma cell viability, migration and colony formation. Most importantly, SHP2 inhibitor 11a-1 suppresses xenografted melanoma tumor growth, as a result of reduced tumor cell proliferation and enhanced tumor cell apoptosis. Taken together, our data reveal SHP2 as a novel target for melanoma and suggest SHP2 inhibitors as potential novel therapeutic agents for melanoma treatment.
Collapse
Affiliation(s)
- Ruo-Yu Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Zhi-Hong Yu
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Lifan Zeng
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Sheng Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Yunpeng Bai
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Jinmin Miao
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Lan Chen
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| | - Jingwu Xie
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Zhong-Yin Zhang
- Department of Medicinal Chemistry and Molecular Pharmacology, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
- Department of Chemistry, Center for Cancer Research, and Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA
| |
Collapse
|
|
39
|
Hepatocyte growth factor renders BRAF mutant human melanoma cell lines resistant to PLX4032 by downregulating the pro-apoptotic BH3-only proteins PUMA and BIM. Cell Death Differ 2016; 23:2054-2062. [PMID: 27689874 DOI: 10.1038/cdd.2016.96] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2016] [Revised: 07/28/2016] [Accepted: 08/02/2016] [Indexed: 12/21/2022] Open
Abstract
A large proportion of melanomas harbour the activating BRAFV600E mutation that renders these cells dependent on MAPK signalling for their survival. Although the highly specific and clinically approved BRAFV600E kinase inhibitor, PLX4032, induces apoptosis of melanoma cells bearing this mutation, the underlying molecular mechanisms are not fully understood. Here, we reveal that PLX4032-induced apoptosis depends on the induction of the pro-apoptotic BH3-only protein PUMA with a minor contribution of its relative BIM. Apoptosis could be significantly augmented when PLX4032 was combined with an inhibitor of the pro-survival protein BCL-XL, whereas neutralization of the pro-survival family member BCL-2 caused no additional cell death. Although the initial response to PLX4032 in melanoma patients is very potent, resistance to the drug eventually develops and relapse occurs. Several factors can cause melanoma cells to develop resistance to PLX4032; one of them is the activation of the receptor tyrosine kinase cMET on melanoma cells by its ligand, hepatocyte growth factor (HGF), provided by the tumour microenvironment or the cancer cells themselves. We found that HGF mediates resistance of cMET-expressing BRAF mutant melanoma cells to PLX4032-induced apoptosis through downregulation of PUMA and BIM rather than by increasing the expression of pro-survival BCL-2-like proteins. These results suggest that resistance to PLX4032 may be overcome by specifically increasing the levels of PUMA and BIM in melanoma cells through alternative signalling cascades or by blocking pro-survival BCL-2 family members with suitable BH3 mimetic compounds.
Collapse
|
|
40
|
Smith BD, Kaufman MD, Leary CB, Turner BA, Wise SC, Ahn YM, Booth RJ, Caldwell TM, Ensinger CL, Hood MM, Lu WP, Patt TW, Patt WC, Rutkoski TJ, Samarakoon T, Telikepalli H, Vogeti L, Vogeti S, Yates KM, Chun L, Stewart LJ, Clare M, Flynn DL. Altiratinib Inhibits Tumor Growth, Invasion, Angiogenesis, and Microenvironment-Mediated Drug Resistance via Balanced Inhibition of MET, TIE2, and VEGFR2. Mol Cancer Ther 2015; 14:2023-34. [PMID: 26285778 DOI: 10.1158/1535-7163.mct-14-1105] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 06/13/2015] [Indexed: 11/16/2022]
Abstract
Altiratinib (DCC-2701) was designed based on the rationale of engineering a single therapeutic agent able to address multiple hallmarks of cancer (1). Specifically, altiratinib inhibits not only mechanisms of tumor initiation and progression, but also drug resistance mechanisms in the tumor and microenvironment through balanced inhibition of MET, TIE2 (TEK), and VEGFR2 (KDR) kinases. This profile was achieved by optimizing binding into the switch control pocket of all three kinases, inducing type II inactive conformations. Altiratinib durably inhibits MET, both wild-type and mutated forms, in vitro and in vivo. Through its balanced inhibitory potency versus MET, TIE2, and VEGFR2, altiratinib provides an agent that inhibits three major evasive (re)vascularization and resistance pathways (HGF, ANG, and VEGF) and blocks tumor invasion and metastasis. Altiratinib exhibits properties amenable to oral administration and exhibits substantial blood-brain barrier penetration, an attribute of significance for eventual treatment of brain cancers and brain metastases.
Collapse
Affiliation(s)
| | | | | | | | | | - Yu Mi Ahn
- Deciphera Pharmaceuticals, Lawrence, Kansas
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Daniel L Flynn
- Deciphera Pharmaceuticals, Lawrence, Kansas. Deciphera Pharmaceuticals, Waltham, Massachusetts.
| |
Collapse
|
|
41
|
Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma. Cancers (Basel) 2015; 7:1586-604. [PMID: 26287245 PMCID: PMC4586785 DOI: 10.3390/cancers7030852] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2015] [Revised: 07/15/2015] [Accepted: 08/10/2015] [Indexed: 01/10/2023] Open
Abstract
Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics.
Collapse
|
|
42
|
van den Hurk K, Balint B, Toomey S, O'Leary PC, Unwin L, Sheahan K, McDermott EW, Murphy I, van den Oord JJ, Rafferty M, FitzGerald DM, Moran J, Cummins R, MacEneaney O, Kay EW, O'Brien CP, Finn SP, Heffron CCBB, Murphy M, Yela R, Power DG, Regan PJ, McDermott CM, O'Keeffe A, Orosz Z, Donnellan PP, Crown JP, Hennessy BT, Gallagher WM. High-throughput oncogene mutation profiling shows demographic differences in BRAF mutation rates among melanoma patients. Melanoma Res 2015; 25:189-99. [PMID: 25746038 DOI: 10.1097/cmr.0000000000000149] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Because of advances in targeted therapies, the clinical evaluation of cutaneous melanoma is increasingly based on a combination of traditional histopathology and molecular pathology. Therefore, it is necessary to expand our knowledge of the molecular events that accompany the development and progression of melanoma to optimize clinical management. The central objective of this study was to increase our knowledge of the mutational events that complement melanoma progression. High-throughput genotyping was adapted to query 159 known single nucleotide mutations in 33 cancer-related genes across two melanoma cohorts from Ireland (n=94) and Belgium (n=60). Results were correlated with various clinicopathological characteristics. A total of 23 mutations in 12 genes were identified, that is--BRAF, NRAS, MET, PHLPP2, PIK3R1, IDH1, KIT, STK11, CTNNB1, JAK2, ALK, and GNAS. Unexpectedly, we discovered significant differences in BRAF, MET, and PIK3R1 mutations between the cohorts. That is, cases from Ireland showed significantly lower (P<0.001) BRAF(V600E) mutation rates (19%) compared with the mutation frequency observed in Belgian patients (43%). Moreover, MET mutations were detected in 12% of Irish cases, whereas none of the Belgian patients harbored these mutations, and Irish patients significantly more often (P=0.027) had PIK3R1-mutant (33%) melanoma versus 17% of Belgian cases. The low incidence of BRAF(V600E)(-) mutant melanoma among Irish patients was confirmed in five independent Irish cohorts, and in total, only 165 of 689 (24%) Irish cases carried mutant BRAF(V600E). Together, our data show that melanoma-driving mutations vary by demographic area, which has important implications for the clinical management of this disease.
Collapse
Affiliation(s)
- Karin van den Hurk
- aOncoMark Ltd, NovaUCD bDepartment of Medical Oncology, Royal College of Surgeons cUCD School of Biomolecular and Biomedical Science, UCD Conway Institute, University College Dublin Departments of dPathology eSurgery fMedical Oncology, St Vincent's University Hospital gDepartment of Histopathology, Royal College of Surgeons in Ireland Education and Research Centre, Beaumont Hospital hDepartment of Histopathology, St James's Hospital iDepartment of Histopathology, Trinity College, Dublin jDepartment of Pathology, Cork University Hospital, Cork Departments of kSurgery lMedical Oncology, University Hospital Galway mDepartment of Medicine, National University of Ireland Galway nDepartment of Histopathology, University Hospital Galway, Galway, Ireland oDepartment of Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands pLaboratory of Morphology and Molecular Pathology, Katholieke Universiteit Leuven, Leuven, Belgium
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
43
|
Petrini I. Biology of MET: a double life between normal tissue repair and tumor progression. ANNALS OF TRANSLATIONAL MEDICINE 2015; 3:82. [PMID: 25992381 DOI: 10.3978/j.issn.2305-5839.2015.03.58] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Accepted: 01/28/2015] [Indexed: 01/30/2023]
Abstract
MNNG HOS transforming gene (MET) is a class IV receptor tyrosine kinase, expressed on the surface of epithelial cells. The interaction with the hepatocyte grow factor (HGF) induces MET dimerization and the activation of multiple intracellular pathways leading to cell proliferation, anti-apoptosis, morphogenic differentiation, motility, invasion, and angiogenesis. Knock out mice have demonstrated that MET is necessary for normal embryogenesis including the formation of striate muscles, liver and trophoblastic structures. The overexpression of MET and HGF are common in solid tumors and contribute to determine their growth. Indeed, MET has been cloned as a transforming gene from a chemically induced human osteosarcoma cell line and therefore is considered a proto-oncogene. Germline MET mutations are characteristic of hereditary papillary kidney cancers and MET amplification is observed in tumors including lung and gastric adenocarcinomas. The inhibition of MET signaling is the target for specific drugs that are raising exciting expectation for medical treatment of cancer.
Collapse
|
|
44
|
Cao HH, Cheng CY, Su T, Fu XQ, Guo H, Li T, Tse AKW, Kwan HY, Yu H, Yu ZL. Quercetin inhibits HGF/c-Met signaling and HGF-stimulated melanoma cell migration and invasion. Mol Cancer 2015; 14:103. [PMID: 25971889 PMCID: PMC4435529 DOI: 10.1186/s12943-015-0367-4] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 04/13/2015] [Indexed: 12/13/2022] Open
Abstract
Background Melanoma is notorious for its propensity to metastasize, which makes treatment extremely difficult. Receptor tyrosine kinase c-Met is activated in human melanoma and is involved in melanoma progression and metastasis. Hepatocyte growth factor (HGF)-mediated activation of c-Met signaling has been suggested as a therapeutic target for melanoma metastasis. Quercetin is a dietary flavonoid that exerts anti-metastatic effect in various types of cancer including melanoma. In a previous report, we demonstrated that quercetin inhibited melanoma cell migration and invasion in vitro, and prevented melanoma cell lung metastasis in vivo. In this study, we sought to determine the involvement of HGF/c-Met signaling in the anti-metastatic action of quercetin in melanoma. Methods Transwell chamber assay was conducted to determine the cell migratory and invasive abilities. Western blotting was performed to determine the expression levels and activities of c-Met and its downstream molecules. And immunoblotting was performed in BS3 cross-linked cells to examine the homo-dimerization of c-Met. Quantitative real-time PCR analysis was carried out to evaluate the mRNA expression level of HGF. Transient transfection was used to overexpress PAK or FAK in cell models. Student’s t-test was used in analyzing differences between two groups. Results Quercetin dose-dependently suppressed HGF-stimulated melanoma cell migration and invasion. Further study indicated that quercetin inhibited c-Met phosphorylation, reduced c-Met homo-dimerization and decreased c-Met protein expression. The effect of quercetin on c-Met expression was associated with a reduced expression of fatty acid synthase. In addition, quercetin suppressed the phosphorylation of c-Met downstream molecules including Gab1 (GRB2-associated-binding protein 1), FAK (Focal Adhesion Kinase) and PAK (p21-activated kinases). More importantly, overexpression of FAK or PAK significantly reduced the inhibitory effect of quercetin on the migration of the melanoma cells. Conclusions Our findings suggest that suppression of the HGF/c-Met signaling pathway contributes to the anti-metastatic action of quercetin in melanoma. Electronic supplementary material The online version of this article (doi:10.1186/s12943-015-0367-4) contains supplementary material, which is available to authorized users.
Collapse
Affiliation(s)
- Hui-Hui Cao
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Chi-Yan Cheng
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Tao Su
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Xiu-Qiong Fu
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Hui Guo
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Ting Li
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Anfernee Kai-Wing Tse
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Hiu-Yee Kwan
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Hua Yu
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| | - Zhi-Ling Yu
- Jockey Club School of Chinese Medicine Building, 7 Baptist University Road, Kowloon Tong, Kowloon, China.
| |
Collapse
|
|
45
|
PAX3 and ETS1 synergistically activate MET expression in melanoma cells. Oncogene 2014; 34:4964-74. [PMID: 25531327 PMCID: PMC4476961 DOI: 10.1038/onc.2014.420] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2013] [Revised: 10/14/2014] [Accepted: 10/21/2014] [Indexed: 12/22/2022]
Abstract
Melanoma is a highly aggressive disease that is difficult to treat due to rapid tumor growth, apoptotic resistance, and high metastatic potential. The MET tyrosine kinase receptor promotes many of these cellular processes, and while MET is often overexpressed in melanoma, the mechanism driving this overexpression is unknown. Since the MET gene is rarely mutated or amplified in melanoma, MET overexpression may be driven by to increased activation through promoter elements. In this report, we find that transcription factors PAX3 and ETS1 directly interact to synergistically activate MET expression. Inhibition of PAX3 and ETS1 expression in melanoma cells leads to a significant reduction of MET receptor levels. The 300 bp 5′ proximal MET promoter contains a PAX3 response element and two ETS1 consensus motifs. While ETS1 can moderately activate both of these sites without cofactors, robust MET promoter activation of the first site is PAX-dependent and requires the presence of PAX3, while the second site is PAX-independent. The induction of MET by ETS1 via this second site is enhanced by HGF-dependent ETS1 activation, thereby MET indirectly promotes its own expression. We further find that expression of a dominant negative ETS1 reduces the ability of melanoma cells to grow both in culture and in vivo. Thus, we discover a pathway where ETS1 advances melanoma through the expression of MET via PAX-dependent and independent mechanisms.
Collapse
|
|
46
|
Della Corte CM, Fasano M, Papaccio F, Ciardiello F, Morgillo F. Role of HGF-MET Signaling in Primary and Acquired Resistance to Targeted Therapies in Cancer. Biomedicines 2014; 2:345-358. [PMID: 28548075 PMCID: PMC5344276 DOI: 10.3390/biomedicines2040345] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Revised: 11/11/2014] [Accepted: 11/17/2014] [Indexed: 02/07/2023] Open
Abstract
The Hepatocyte growth factor (HGF)-mesenchymal-epithelial transition (MET) pathway is deregulated in several cancers and is associated with aggressive phenotype and worse prognosis. MET, a tyrosine kinase receptor activated by HGF, plays a physiological role in embryogenesis, promoting cell growth, survival and motility. HGF-MET aberrant activation in tumorigenesis acts through various mechanisms: paracrine/autocrine HGF production, MET overexpression, MET germ-line and sporadic mutations and cross-talk with other growth factor receptors. In addition, MET activation could represent a mechanism of escape from other targeted therapies, through receptor amplification or over-stimulation by the ligand, as demonstrated in non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) models with acquired resistance to epidermal growth factor receptor (EGFR) inhibitors and also in models of melanoma resistant to the BRAF inhibitor vemurafenib. As a consequence, a lot of molecules targeting MET signaling are under clinical investigation as single agent or in combination with other targeted drugs. Patient selection, based on MET expression on tumor samples (eventually, by re-biopsy of new metastatic sites), and pharmacokinetic/pharmacodynamic markers are needed. Authors review the latest data on the role of MET and the molecular mechanism underlying primary or acquired resistance to biological agents, focusing on NSCLC, CRC and melanoma.
Collapse
Affiliation(s)
- Carminia Maria Della Corte
- Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara", Second University of Naples, Napoli 80131, Italy.
| | - Morena Fasano
- Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara", Second University of Naples, Napoli 80131, Italy.
| | - Federica Papaccio
- Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara", Second University of Naples, Napoli 80131, Italy.
| | - Fortunato Ciardiello
- Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara", Second University of Naples, Napoli 80131, Italy.
| | - Floriana Morgillo
- Medical Oncology, Department of Experimental and Internal Medicine "F. Magrassi e A. Lanzara", Second University of Naples, Napoli 80131, Italy.
| |
Collapse
|
|
47
|
Kang ST, Kim EY, Archary R, Jung H, Park CH, Yun CS, Hwang JY, Choi SU, Chae C, Lee CO, Kim HR, Ha JD, Ryu D, Cho SY. Discovery of substituted 6-pheny-3H-pyridazin-3-one derivatives as novel c-Met kinase inhibitors. Bioorg Med Chem Lett 2014; 24:5093-7. [DOI: 10.1016/j.bmcl.2014.08.067] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Revised: 08/18/2014] [Accepted: 08/29/2014] [Indexed: 12/15/2022]
|
|
48
|
Puzanov I, Sosman J, Santoro A, Saif MW, Goff L, Dy GK, Zucali P, Means-Powell JA, Ma WW, Simonelli M, Martell R, Chai F, Lamar M, Savage RE, Schwartz B, Adjei AA. Phase 1 trial of tivantinib in combination with sorafenib in adult patients with advanced solid tumors. Invest New Drugs 2014; 33:159-68. [PMID: 25294187 PMCID: PMC4295023 DOI: 10.1007/s10637-014-0167-5] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 09/29/2014] [Indexed: 01/24/2023]
Abstract
PURPOSE This phase I study evaluated the safety, tolerability, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) of tivantinib combined with sorafenib in patients with advanced solid tumors. MATERIALS AND METHODS A standard 3 + 3 dose escalation design was used. At the RP2D, expansion cohorts in 5 tumor types could be enrolled. Pharmacogenetic and pharmacodynamic analysis were performed. RESULTS Eighty-seven patients received the study treatment. The combination had no unexpected toxicities. The most common treatment-related adverse events (AE) were rash (40 %), diarrhea (38 %), and anorexia (33 %). The RP2D was tivantinib 360 mg BID and sorafenib 400 mg BID for all cancer histologies, except in hepatocellular carcinoma (HCC) patients tivantinib was 240 mg BID plus sorafenib 400 mg BID. The overall response rate was 12 % in all patients, 26 % in melanoma, 15 % in renal cell carcinoma (RCC), 10 % in HCC, and 0 % in other patients. Disease control rate (CR, PR and SD ≥8 weeks) was 58 % in all patients, 90 % in RCC, 65 % in HCC, 63 % in melanoma, 40 % in breast cancer, and 8 % in NSCLC patients. CONCLUSIONS The combination treatment could be administered at full standard single-agent doses in all patients except those with HCC, where tivantinib was lowered to 240 mg BID. Preliminary evidence of anticancer activity was observed in patients with RCC, HCC, and melanoma, including patients refractory to sorafenib and/or other anti-VEGF pathway therapies. The combination treatment has therapeutic potential in treating a variety of solid tumors.
Collapse
Affiliation(s)
- Igor Puzanov
- Vanderbilt University Medical Center, 2220 Pierce Avenue, 777 Preston Research Building, Nashville, TN, USA,
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
49
|
Novel secondary somatic mutations in Ewing's sarcoma and desmoplastic small round cell tumors. PLoS One 2014; 9:e93676. [PMID: 25119929 PMCID: PMC4131855 DOI: 10.1371/journal.pone.0093676] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Accepted: 03/05/2014] [Indexed: 12/21/2022] Open
Abstract
BACKGROUND Ewing's sarcoma (ES) and desmoplastic small round cell tumors (DSRCT) are small round blue cell tumors driven by an N-terminal containing EWS translocation. Very few somatic mutations have been reported in ES, and none have been identified in DSRCT. The aim of this study is to explore potential actionable mutations in ES and DSRCT. METHODOLOGY Twenty eight patients with ES or DSRCT had tumor tissue available that could be analyzed by one of the following methods: 1) Next-generation exome sequencing platform; 2) Multiplex PCR/Mass Spectroscopy; 3) Polymerase chain reaction (PCR)-based single- gene mutation screening; 4) Sanger sequencing; 5) Morphoproteomics. PRINCIPAL FINDINGS Novel somatic mutations were identified in four out of 18 patients with advanced ES and two of 10 patients with advanced DSRCT (six out of 28 (21.4%));KRAS (n = 1), PTPRD (n = 1), GRB10 (n = 2), MET (n = 2) and PIK3CA (n = 1). One patient with both PTPRD and GRB10 mutations and one with a GRB10 mutation achieved a complete remission (CR) on an Insulin like growth factor 1 receptor (IGF1R) inhibitor based treatment. One patient, who achieved a partial remission (PR) with IGF1R inhibitor treatment, but later developed resistance, demonstrated a KRAS mutation in the post-treatment resistant tumor, but not in the pre-treatment tumor suggesting that the RAF/RAS/MEK pathway was activated with progression. CONCLUSIONS We have reported several different mutations in advanced ES and DSRCT that have direct implications for molecularly-directed targeted therapy. Our technology agnostic approach provides an initial mutational roadmap used in the path towards individualized combination therapy.
Collapse
|
|
50
|
Pastushenko I, Vermeulen PB, Van den Eynden GG, Rutten A, Carapeto FJ, Dirix LY, Van Laere S. Mechanisms of tumour vascularization in cutaneous malignant melanoma: clinical implications. Br J Dermatol 2014; 171:220-33. [PMID: 24641095 DOI: 10.1111/bjd.12973] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/11/2014] [Indexed: 01/02/2023]
Abstract
Malignant melanoma represents < 10% of all skin cancers but is responsible for the majority of skin-cancer-related deaths. Metastatic melanoma has historically been considered as one of the most therapeutically challenging malignancies. Fortunately, for the first time after decades of basic research and clinical investigation, new drugs have produced major clinical responses. Angiogenesis has been considered an important target for cancer treatment. Initial efforts have focused primarily on targeting endothelial and tumour-related vascular endothelial growth factor signalling. Here, we review different mechanisms of tumour vascularization described in melanoma and discuss the potential clinical implications.
Collapse
Affiliation(s)
- I Pastushenko
- Department of Dermatology, Hospital Clínico Universitario 'Lozano Blesa', Zaragoza, 50009, Spain
| | | | | | | | | | | | | |
Collapse
|