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1
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Chen X, Li Y, Wang H, Wen K. Evaluation of cytomorphological examination in the diagnosis of pleural effusion. Clin Exp Med 2025; 25:112. [PMID: 40208379 DOI: 10.1007/s10238-025-01642-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Accepted: 03/17/2025] [Indexed: 04/11/2025]
Abstract
Cytological examination serves as a crucial diagnostic tool for pleural effusion, with its diagnostic efficacy influenced by variations in specimen processing and staining techniques. Cellular morphological analysis of pleural effusions was performed using Wright-Giemsa staining to assess its diagnostic accuracy and clinical utility in differentiating the various etiologies of exudative pleural effusion. A routine examination was conducted on 2305 cases of unexplained pleural effusion, followed by cellular classification and morphological analysis in 1376 cases identified as exudative effusion. Among the 479 patients with malignant tumors, cytomorphological examination identified malignant cells in 295 patients, resulting in a clinical diagnosis coincidence rate of 98.6%. Abnormal cells, including malignant and heterogeneous nuclear cells, were observed in 364 cases, yielding a detection rate of 76.0%. The proportion of positive malignant cells in the newly diagnosed patient group was significantly higher than that in the previously diagnosed group (P < 0.01). Cytological analysis revealed the presence of bacteria, fungi, and phagocytes in 51 out of 1376 cases. The positivity rate for multiple bacterial infections detected through cytology was significantly greater than that identified by culture (P < 0.01). Additionally, various special morphologies and pathogens, which are rare in clinical practice, were detected, including mixed metastasis of small cell lung carcinoma and adenocarcinoma cells, as well as concurrent infections with Talaromyces marneffei and Pneumocystis jirovecii. This method enables the rapid and comprehensive differentiation between malignant tumors, tuberculosis, pneumonia, and rare exudative pleural effusions resulting from specific clinical conditions.
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Affiliation(s)
- Xiaoting Chen
- Medical Laboratory Center, Jinjiang Municipal Hospital, No. 16, Luoshan Section, Jinguang Road, Jinjiang, Quanzhou, 362200, Fujian Province, China.
| | - Yongyu Li
- Medical Laboratory Center, Jinjiang Municipal Hospital, No. 16, Luoshan Section, Jinguang Road, Jinjiang, Quanzhou, 362200, Fujian Province, China
| | - Hongyan Wang
- Medical Laboratory Center, Jinjiang Municipal Hospital, No. 16, Luoshan Section, Jinguang Road, Jinjiang, Quanzhou, 362200, Fujian Province, China
| | - Kaizhen Wen
- Medical Laboratory Center, Jinjiang Municipal Hospital, No. 16, Luoshan Section, Jinguang Road, Jinjiang, Quanzhou, 362200, Fujian Province, China
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2
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Qin S, Xie L, Tang M, Ni H, Yang T. Identification of a 7H-pyrrolo[2,3-d]pyrimidin derivatives as selective type II c-Met/Axl inhibitors with potent antitumor efficacy. Bioorg Chem 2025; 156:108187. [PMID: 39864372 DOI: 10.1016/j.bioorg.2025.108187] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/03/2025] [Accepted: 01/17/2025] [Indexed: 01/28/2025]
Abstract
In this study, we reported the discovery of a novel type II c-Met/Axl inhibitor, characterized by using 4-amino-7H-pyrrolo[2,3-d]pyrimidine as a hinge region binder. Through a systematic exploration of the structure-activity relationship, based on the clinically reported c-Met inhibitor BMS-777607, we identified the optimized compound 22a. 22a exhibited remarkable potency against c-Met and Axl kinases, with IC50 values of 1 nM and 10 nM, respectively, and demonstrated over 100-fold selectivity to other members of the TAM subfamily. Furthermore, compared to cabozantinib, compound 22a displayed superior anti-tumor proliferation activity across a range of solid tumors. 22a demonstrated excellent drug-like properties, achieving a bioavailability of 174.2 % in rats. In established MKN-45 and HCT116 xenograft tumor models, compound 22a achieved tumor growth inhibition (TGI) rates of 98.2 % and 87.2 %, respectively, at a dosage of 1 mg/kg. Taken together, compound 22a is a selective dual c-Met/Axl inhibitor with significant potential as a clinical candidate.
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Affiliation(s)
- Songhui Qin
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Lixin Xie
- Department of Biotherapy, Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Minghai Tang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu 610041, China
| | - Hengfan Ni
- Pharmacy Department of West China Hospital, Sichuan University, China
| | - Tao Yang
- Center for Preclinical Safety Evaluation of Drugs, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu 610041, China.
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3
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Mer AH, Mirzaei Y, Misamogooe F, Bagheri N, Bazyari A, Keshtkaran Z, Meyfour A, Shahedi A, Amirkhani Z, Jafari A, Barpour N, Jahandideh S, Rezaei B, Nikmanesh Y, Abdollahpour-Alitappeh M. Progress of antibody-drug conjugates (ADCs) targeting c-Met in cancer therapy; insights from clinical and preclinical studies. Drug Deliv Transl Res 2024; 14:2963-2988. [PMID: 38597995 DOI: 10.1007/s13346-024-01564-3] [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: 02/29/2024] [Indexed: 04/11/2024]
Abstract
The cell-surface receptor tyrosine kinase c-mesenchymal-epithelial transition factor (c-Met) is overexpressed in a wide range of solid tumors, making it an appropriate target antigen for the development of anticancer therapeutics. Various antitumor c-Met-targeting therapies (including monoclonal antibodies [mAbs] and tyrosine kinases) have been developed for the treatment of c-Met-overexpressing tumors, most of which have so far failed to enter the clinic because of their efficacy and complications. Antibody-drug conjugates (ADCs), a new emerging class of cancer therapeutic agents that harness the target specificity of mAbs to deliver highly potent small molecules to the tumor with the minimal damage to normal cells, could be an attractive therapeutic approach to circumvent these limitations in patients with c-Met-overexpressing tumors. Of great note, there are currently nine c-Met-targeting ADCs being examined in different phases of clinical studies as well as eight preclinical studies for treating various solid tumors. The purpose of this study is to present a broad overview of clinical- and preclinical-stage c-Met-targeting ADCs.
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Affiliation(s)
- Ali Hussein Mer
- Department of Nursing, Mergasour Technical Institute, Erbil Polytechnic University, Erbil, Iraq
| | - Yousef Mirzaei
- Department of Medical Biochemical Analysis, Cihan University-Erbil, Erbil, Kurdistan Region, Iraq
| | - Fatemeh Misamogooe
- Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran
| | - Nader Bagheri
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, 8813733450, Iran
| | - Ahmadreza Bazyari
- Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Keshtkaran
- Department of Nursing, School of Nursing and Midwifery, Community Based Psychiatric Care Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Anna Meyfour
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Shahedi
- Student Research Committee, Larestan University of Medical Sciences, Larestan, Iran
| | - Zahra Amirkhani
- Department of Nursing, School of Nursing, Larestan University of Medical Sciences, Larestan, Iran
| | - Ameneh Jafari
- Proteomics Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Nesa Barpour
- Department of Genetics, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Saeed Jahandideh
- Department of Research and Development, Orchidgene Co, Tehran, 1387837584, Iran
| | - Behzad Rezaei
- Laparoscopy Research Center, Department of Surgery, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Fars Province, Iran
| | - Yousef Nikmanesh
- Gastroenterohepatology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.
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Chang YC, Liu CT, Yu CY, Sung WW. NPS-1034 Exerts Therapeutic Efficacy in Renal Cell Carcinoma Through Multiple Targets of MET, AXL, and TNFRSF1A Signaling in a Metastatic Model. Cells 2024; 13:1713. [PMID: 39451232 PMCID: PMC11506434 DOI: 10.3390/cells13201713] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Revised: 08/20/2024] [Accepted: 10/14/2024] [Indexed: 10/26/2024] Open
Abstract
Renal cell carcinoma (RCC) has diverse pathological subtypes, most of which have a poor prognosis. Patients with advanced RCC require systemic therapies for disease control. Although targeted therapies and immune checkpoint inhibitors have shown therapeutic efficacy, patients eventually succumb to disease progression. Therefore, additional therapies targeting different pathways are needed to provide more therapeutic options for sequential treatment. Our study explored the biological mechanisms and therapeutic outcomes for NPS-1034, a dual MET/AXL inhibitor, in RCC, both in vivo and in vitro. Our results showed that NPS-1034 can significantly inhibit tumor proliferation and induce cancer cell apoptosis. Besides MET and AXL, known targets of NPS-1034, we identified TNFRSF1A as another target gene inhibited by NPS-1034 via antibody arrays. This was further supported by next-generation sequencing, showing that the TNF signaling pathway is one of the most significant NPS-1034-regulated pathways. Furthermore, one of the identified target genes, GADD45A, responsible for NPS-1034 anticancer properties, was significantly associated with patient survival in RCC. GADD45A expression was significantly upregulated via NPS-1034 and downregulated via TNFRSF1A overexpression. Finally, its therapeutic efficacy was demonstrated in vivo, showing that NPS-1034 significantly alleviated the tumor burden and inhibited cell proliferation in a lung metastatic animal model. In conclusion, we explored the therapeutic mechanism of NPS-1034 and found that it targets not only MET and AXL but also TNFRSF1A. In a lung metastatic animal model, we confirmed that NPS-1034 is a potential candidate for systemic therapy in RCC.
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MESH Headings
- Carcinoma, Renal Cell/drug therapy
- Carcinoma, Renal Cell/pathology
- Carcinoma, Renal Cell/metabolism
- Carcinoma, Renal Cell/genetics
- Humans
- Axl Receptor Tyrosine Kinase
- Receptor Protein-Tyrosine Kinases/metabolism
- Receptor Protein-Tyrosine Kinases/antagonists & inhibitors
- Animals
- Kidney Neoplasms/pathology
- Kidney Neoplasms/drug therapy
- Kidney Neoplasms/metabolism
- Kidney Neoplasms/genetics
- Proto-Oncogene Proteins/metabolism
- Proto-Oncogene Proteins/genetics
- Proto-Oncogene Proteins/antagonists & inhibitors
- Proto-Oncogene Proteins c-met/metabolism
- Proto-Oncogene Proteins c-met/antagonists & inhibitors
- Proto-Oncogene Proteins c-met/genetics
- Signal Transduction/drug effects
- Cell Line, Tumor
- Mice
- Cell Proliferation/drug effects
- Receptors, Tumor Necrosis Factor, Type I/metabolism
- Receptors, Tumor Necrosis Factor, Type I/genetics
- Apoptosis/drug effects
- Neoplasm Metastasis
- Xenograft Model Antitumor Assays
- Gene Expression Regulation, Neoplastic/drug effects
- Mice, Nude
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Affiliation(s)
- Ya-Chuan Chang
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-C.C.); (C.-T.L.); (C.-Y.Y.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Chien-Te Liu
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-C.C.); (C.-T.L.); (C.-Y.Y.)
| | - Chia-Ying Yu
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-C.C.); (C.-T.L.); (C.-Y.Y.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
| | - Wen-Wei Sung
- School of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan; (Y.-C.C.); (C.-T.L.); (C.-Y.Y.)
- Department of Urology, Chung Shan Medical University Hospital, Taichung 40201, Taiwan
- Institute of Medicine, Chung Shan Medical University, Taichung 40201, Taiwan
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Chilamakuri R, Agarwal S. Repurposing of c-MET Inhibitor Tivantinib Inhibits Pediatric Neuroblastoma Cellular Growth. Pharmaceuticals (Basel) 2024; 17:1350. [PMID: 39458991 PMCID: PMC11510580 DOI: 10.3390/ph17101350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 09/22/2024] [Accepted: 10/01/2024] [Indexed: 10/28/2024] Open
Abstract
Background: Dysregulation of receptor tyrosine kinase c-MET is known to promote tumor development by stimulating oncogenic signaling pathways in different cancers, including pediatric neuroblastoma (NB). NB is an extracranial solid pediatric cancer that accounts for almost 15% of all pediatric cancer-related deaths, with less than a 50% long-term survival rate. Results: In this study, we analyzed a large cohort of primary NB patient data and revealed that high MET expression strongly correlates with poor overall survival, disease progression, relapse, and high MYCN levels in NB patients. To determine the effects of c-MET in NB, we repurposed a small molecule inhibitor, tivantinib, and found that c-MET inhibition significantly inhibits NB cellular growth. Tivantinib significantly blocks NB cell proliferation and 3D spheroid tumor formation and growth in different MYCN-amplified and MYCN-non-amplified NB cell lines. Furthermore, tivantinib blocks the cell cycle at the G2/M phase transition and induces apoptosis in different NB cell lines. As expected, c-MET inhibition by tivantinib inhibits the expression of multiple genes in PI3K, STAT, and Ras cell signaling pathways. Conclusions: Overall, our data indicate that c-MET directly regulates NB growth and 3D spheroid growth, and c-MET inhibition by tivantinib may be an effective therapeutic approach for high-risk NB. Further developing c-MET targeted therapeutic approaches and combining them with current therapies may pave the way for effectively translating novel therapies for NB and other c-MET-driven cancers.
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Affiliation(s)
| | - Saurabh Agarwal
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John’s University, New York, NY 11439, USA
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Lu S, Yin Z, Chen J, Wu L, Sun Y, Gao X, Huang P, Jordan JT, Plotkin SR, Xu L. Integrating Ataxia Evaluation into Tumor-Induced Hearing Loss Model to Comprehensively Study NF2-Related Schwannomatosis. Cancers (Basel) 2024; 16:1961. [PMID: 38893082 PMCID: PMC11171041 DOI: 10.3390/cancers16111961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 06/21/2024] Open
Abstract
NF2-related Schwannomatosis (NF2-SWN) is a disease that needs new solutions. The hallmark of NF2-SWN, a dominantly inherited neoplasia syndrome, is bilateral vestibular schwannomas (VSs), which progressively enlarge, leading to sensorineural hearing loss, tinnitus, facial weakness, and pain that translates to social impairment and clinical depression. Standard treatments for growing VSs include surgery and radiation therapy (RT); however, both carry the risk of further nerve damage that can result in deafness and facial palsy. The resultant suffering and debility, in combination with the paucity of therapeutic options, make the effective treatment of NF2-SWN a major unmet medical need. A better understanding of these mechanisms is essential to developing novel therapeutic targets to control tumor growth and improve patients' quality of life. Previously, we developed the first orthotopic cerebellopontine angle mouse model of VSs, which faithfully mimics tumor-induced hearing loss. In this model, we observed that mice exhibit symptoms of ataxia and vestibular dysfunction. Therefore, we further developed a panel of five tests suitable for the mouse VS model and investigated how tumor growth and treatment affect gait, coordination, and motor function. Using this panel of ataxia tests, we demonstrated that both ataxia and motor function deteriorated concomitantly with tumor progression. We further demonstrated that (i) treatment with anti-VEGF resulted in tumor size reduction, mitigated ataxia, and improved rotarod performance; (ii) treatment with crizotinib stabilized tumor growth and led to improvements in both ataxia and rotarod performance; and (iii) treatment with losartan did not impact tumor growth nor ameliorate ataxia or motor function. Our studies demonstrated that these methods, paired with hearing tests, enable a comprehensive evaluation of tumor-induced neurological deficits and facilitate the assessment of the effectiveness of novel therapeutics to improve NF2 treatments.
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Affiliation(s)
- Simeng Lu
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Zhenzhen Yin
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Jie Chen
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Limeng Wu
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Stomatology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100073, China
| | - Yao Sun
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Radiation Oncology, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin Clinical Research for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin 300060, China
| | - Xing Gao
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
- Department of Oral and Maxillofacial Surgery, Xiangya Hospital, Central South University, Changsha 410008, China
| | - Peigen Huang
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
| | - Justin T. Jordan
- Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Scott R. Plotkin
- Stephen E. and Catherine Pappas Center for Neuro-Oncology, Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Lei Xu
- Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA
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7
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Xia S, Duan W, Xu M, Li M, Tang M, Wei S, Lin M, Li E, Liu W, Wang Q. Mesothelin promotes brain metastasis of non-small cell lung cancer by activating MET. J Exp Clin Cancer Res 2024; 43:103. [PMID: 38570866 PMCID: PMC10988939 DOI: 10.1186/s13046-024-03015-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Accepted: 03/18/2024] [Indexed: 04/05/2024] Open
Abstract
BACKGROUND Brain metastasis (BM) is common among cases of advanced non-small cell lung cancer (NSCLC) and is the leading cause of death for these patients. Mesothelin (MSLN), a tumor-associated antigen expressed in many solid tumors, has been reported to be involved in the progression of multiple tumors. However, its potential involvement in BM of NSCLC and the underlying mechanism remain unknown. METHODS The expression of MSLN was validated in clinical tissue and serum samples using immunohistochemistry and enzyme-linked immunosorbent assay. The ability of NSCLC cells to penetrate the blood-brain barrier (BBB) was examined using an in vitro Transwell model and an ex vivo multi-organ microfluidic bionic chip. Immunofluorescence staining and western blotting were used to detect the disruption of tight junctions. In vivo BBB leakiness assay was performed to assess the barrier integrity. MET expression and activation was detected by western blotting. The therapeutic efficacy of drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) on BM was evaluated in animal studies. RESULTS MSLN expression was significantly elevated in both serum and tumor tissue samples from NSCLC patients with BM and correlated with a poor clinical prognosis. MSLN significantly enhanced the brain metastatic abilities of NSCLC cells, especially BBB extravasation. Mechanistically, MSLN facilitated the expression and activation of MET through the c-Jun N-terminal kinase (JNK) signaling pathway, which allowed tumor cells to disrupt tight junctions and the integrity of the BBB and thereby penetrate the barrier. Drugs targeting MSLN (anetumab) and MET (crizotinib/capmatinib) effectively blocked the development of BM and prolonged the survival of mice. CONCLUSIONS Our results demonstrate that MSLN plays a critical role in BM of NSCLC by modulating the JNK/MET signaling network and thus, provides a potential novel therapeutic target for preventing BM in NSCLC patients.
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Affiliation(s)
- Shengkai Xia
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Wenzhe Duan
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Mingxin Xu
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Mengqi Li
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Mengyi Tang
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Song Wei
- Department of Oncology, Beijing Chest Hospital, Capital Medical University, Beijing, China
| | - Manqing Lin
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China
| | - Encheng Li
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
| | - Wenwen Liu
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
- Department of Scientific Research Center, The Second Hospital, Dalian Medical University, Dalian, China.
| | - Qi Wang
- Department of Respiratory Medicine, The Second Hospital, Dalian Medical University, Dalian, China.
- Department of Scientific Research Center, The Second Hospital, Dalian Medical University, Dalian, China.
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8
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Moosburner M, Alibegovic L, Hasselmann K, Gaiderov A, Hildebrand J, Philippou-Massier J, Blum H, Fischer L, Dreyling M, Silkenstedt E. Combined treatment with crizotinib and temsirolimus is an effective strategy in mantle cell lymphoma and can overcome acquired resistance to temsirolimus. Hematol Oncol 2023; 41:858-868. [PMID: 37300279 DOI: 10.1002/hon.3194] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 05/12/2023] [Accepted: 05/19/2023] [Indexed: 06/12/2023]
Abstract
Constitutive activation of the PI3K/AKT/mTOR-pathway plays an important role in the pathogenesis of mantle cell lymphoma (MCL), leading to approval of the mTOR inhibitor temsirolimus for relapsed or refractory MCL. Yet, despite favorable initial response rates, early relapses under treatment have been observed. Therefore, understanding the underlying mechanisms of temsirolimus resistance and developing strategies to overcome it is highly warranted. Here, we established a new temsirolimus-resistant MCL cell line to evaluate the molecular background of resistance to this drug. Transcriptome profiling and gene set enrichment analysis comparing temsirolimus-sensitive and -resistant cell lines showed significant upregulation of PI3K/AKT/mTor-, RAS signaling- and the RTK-dependent PDGFR-, FGFR-, Met- and ALK-signaling-pathways in the resistant cells. Furthermore, MET, known as important proto-oncogene and mediator of drug resistance, was among the most upregulated genes in the resistant cells. Importantly, Met protein was overexpressed in both, MCL cells with acquired as well as intrinsic temsirolimus resistance, but could not be detected in any of the temsirolimus sensitive ones. Combined pharmacological inhibition of mTOR and Met signaling with temsirolimus and the RTK inhibitor crizotinib significantly restored sensitivity to temsirolimus. Furthermore, this combined treatment proved to be synergistic in all MCL cell lines investigated and was also active in primary MCL cells. In summary, we showed for the first time that overexpression of MET plays an important role for mediating temsirolimus resistance in MCL and combined treatment with temsirolimus and crizotinib is a very promising therapeutic approach for MCL and an effective strategy to overcome temsirolimus resistance.
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Affiliation(s)
- Marie Moosburner
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
| | - Lamija Alibegovic
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
| | - Korbinian Hasselmann
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
| | - Anton Gaiderov
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
| | - Johannes Hildebrand
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
| | - Julia Philippou-Massier
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, University of Munich, Munich, Germany
| | - Helmut Blum
- Laboratory for Functional Genome Analysis (LAFUGA), Gene Center, University of Munich, Munich, Germany
| | - Luca Fischer
- Department of Medicine III, LMU University Hospital Großhadern of the Ludwig-Maximilians-University, Munich, Germany
| | - Martin Dreyling
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
- Department of Medicine III, LMU University Hospital Großhadern of the Ludwig-Maximilians-University, Munich, Germany
| | - Elisabeth Silkenstedt
- Department of Medicine III, Laboratory for Experimental Leukemia and Lymphoma Research (ELLF), Ludwig-Maximilians-University, Munich, Germany
- Department of Medicine III, LMU University Hospital Großhadern of the Ludwig-Maximilians-University, Munich, Germany
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9
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Meyer C, McCoy M, Li L, Posner B, Westover KD. LIMS-Kinase provides sensitive and generalizable label-free in vitro measurement of kinase activity using mass spectrometry. CELL REPORTS. PHYSICAL SCIENCE 2023; 4:101599. [PMID: 38213501 PMCID: PMC10783653 DOI: 10.1016/j.xcrp.2023.101599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Measurements of kinase activity are important for kinase-directed drug development, analysis of inhibitor structure and function, and understanding mechanisms of drug resistance. Sensitive, accurate, and miniaturized assay methods are crucial for these investigations. Here, we describe a label-free, high-throughput mass spectrometry-based assay for studying individual kinase enzymology and drug discovery in a purified system, with a focus on validated drug targets as benchmarks. We demonstrate that this approach can be adapted to many known kinase substrates and highlight the benefits of using mass spectrometry to measure kinase activity in vitro, including increased sensitivity. We speculate that this approach to measuring kinase activity will be generally applicable across most of the kinome, enabling research on understudied kinases and kinase drug discovery.
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Affiliation(s)
- Cynthia Meyer
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Melissa McCoy
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Lianbo Li
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Bruce Posner
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
| | - Kenneth D. Westover
- Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
- Department of Radiation Oncology, The University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA
- X (formerly Twitter): @KENWESTOVER
- Lead contact
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Altintas DM, Comoglio PM. An Observatory for the MET Oncogene: A Guide for Targeted Therapies. Cancers (Basel) 2023; 15:4672. [PMID: 37760640 PMCID: PMC10526818 DOI: 10.3390/cancers15184672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Revised: 09/13/2023] [Accepted: 09/20/2023] [Indexed: 09/29/2023] Open
Abstract
The MET proto-oncogene encodes a pivotal tyrosine kinase receptor, binding the hepatocyte growth factor (HGF, also known as scatter factor, SF) and governing essential biological processes such as organogenesis, tissue repair, and angiogenesis. The pleiotropic physiological functions of MET explain its diverse role in cancer progression in a broad range of tumors; genetic/epigenetic alterations of MET drive tumor cell dissemination, metastasis, and acquired resistance to conventional and targeted therapies. Therefore, targeting MET emerged as a promising strategy, and many efforts were devoted to identifying the optimal way of hampering MET signaling. Despite encouraging results, however, the complexity of MET's functions in oncogenesis yields intriguing observations, fostering a humbler stance on our comprehension. This review explores recent discoveries concerning MET alterations in cancer, elucidating their biological repercussions, discussing therapeutic avenues, and outlining future directions. By contextualizing the research question and articulating the study's purpose, this work navigates MET biology's intricacies in cancer, offering a comprehensive perspective.
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Affiliation(s)
| | - Paolo M. Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, 20139 Milano, Italy;
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11
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Ebrahimi N, Fardi E, Ghaderi H, Palizdar S, Khorram R, Vafadar R, Ghanaatian M, Rezaei-Tazangi F, Baziyar P, Ahmadi A, Hamblin MR, Aref AR. Receptor tyrosine kinase inhibitors in cancer. Cell Mol Life Sci 2023; 80:104. [PMID: 36947256 PMCID: PMC11073124 DOI: 10.1007/s00018-023-04729-4] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 01/31/2023] [Accepted: 02/13/2023] [Indexed: 03/23/2023]
Abstract
Targeted therapy is a new cancer treatment approach, involving drugs that particularly target specific proteins in cancer cells, such as receptor tyrosine kinases (RTKs) which are involved in promoting growth and proliferation, Therefore inhibiting these proteins could impede cancer progression. An understanding of RTKs and the relevant signaling cascades, has enabled the development of many targeted drug therapies employing RTK inhibitors (RTKIs) some of which have entered clinical application. Here we discuss RTK structures, activation mechanisms and functions. Moreover, we cover the potential effects of combination drug therapy (including chemotherapy or immunotherapy agents with one RTKI or multiple RTKIs) especially for drug resistant cancers.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Isfahan, Iran
| | - Elmira Fardi
- Medical Branch, Islamic Azad University of Tehran, Tehran, Iran
| | - Hajarossadat Ghaderi
- Laboratory of Regenerative and Medical Innovation, Pasteur Institute of Iran, Tehran, Iran
| | - Sahar Palizdar
- Division of Microbiology, Faculty of Basic Sciences, Islamic Azad University of Tehran East Branch, Tehran, Iran
| | - Roya Khorram
- Bone and Joint Diseases Research Center, Department of Orthopedic Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Reza Vafadar
- Department of Orthopeadic Surgery, Kerman University of Medical Sciences, Kerman, Iran
| | - Masoud Ghanaatian
- Master 1 Bio-Santé-Parcours Toulouse Graduate School of Cancer, Ageing and Rejuvenation (CARe), Université Toulouse III-Paul Sabatier, Toulouse, France
| | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Payam Baziyar
- Department of Molecular and Cell Biology, Faculty of Basic Science, Uinversity of Mazandaran, Babolsar, Iran
| | - Amirhossein Ahmadi
- Department of Biological Science and Technology, Faculty of Nano and Bio Science and Technology, Persian Gulf University, Bushehr, 75169, Iran.
| | - Michael R Hamblin
- Laser Research Centre, Faculty of Health Science, University of Johannesburg, Doornfontein, 2028, South Africa.
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA.
- Translational Medicine Group, Xsphera Biosciences, 6 Tide Street, Boston, MA, 02210, USA.
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12
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An In Vitro Analysis of TKI-Based Sequence Therapy in Renal Cell Carcinoma Cell Lines. Int J Mol Sci 2023; 24:ijms24065648. [PMID: 36982721 PMCID: PMC10058472 DOI: 10.3390/ijms24065648] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 03/01/2023] [Accepted: 03/09/2023] [Indexed: 03/18/2023] Open
Abstract
The tyrosine kinase inhibitor (TKI) cabozantinib might impede the growth of the sunitinib-resistant cell lines by targeting MET and AXL overexpression in metastatic renal cell carcinoma (mRCC). We studied the role of MET and AXL in the response to cabozantinib, particularly following long-term administration with sunitinib. Two sunitinib-resistant cell lines, 786-O/S and Caki-2/S, and the matching 786-O/WT and Caki-2/WT cells were exposed to cabozantinib. The drug response was cell-line-specific. The 786-O/S cells were less growth-inhibited by cabozantinib than 786-O/WT cells (p-value = 0.02). In 786-O/S cells, the high level of phosphorylation of MET and AXL was not affected by cabozantinib. Despite cabozantinib hampering the high constitutive phosphorylation of MET, the Caki-2 cells showed low sensitivity to cabozantinib, and this was independent of sunitinib pretreatment. In both sunitinib-resistant cell lines, cabozantinib increased Src-FAK activation and impeded mTOR expression. The modulation of ERK and AKT was cell-line-specific, mirroring the heterogeneity among the patients. Overall, the MET- and AXL-driven status did not affect cell responsiveness to cabozantinib in the second-line treatment. The activation of Src-FAK might counteract cabozantinib activity and contribute to tumor survival and may be considered an early indicator of therapy response.
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13
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Sakamoto M, Patil T. MET alterations in advanced non-small cell lung cancer. Lung Cancer 2023; 178:254-268. [PMID: 36924573 DOI: 10.1016/j.lungcan.2023.02.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/23/2023] [Accepted: 02/21/2023] [Indexed: 03/05/2023]
Abstract
Targeting the MET pathway in advanced NSCLC has been of particular interest due to its role as both a primary oncogenic driver and secondary oncogenic driver of acquired resistance. Activation of the MET pathway can occur through several mechanisms, which can complicate the diagnostic and treatment approach. Recently, several MET-directed therapies have been developed with promising results. In this narrative review, we summarize the biology and mechanism of MET as a clinically relevant driver mutation, distinct MET alterations including diagnostic challenges, significance in the setting of acquired resistance, and novel treatment strategies in advanced NSCLC.
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Affiliation(s)
- Mandy Sakamoto
- Department of Medicine, Division of Medical Oncology, United States
| | - Tejas Patil
- Department of Medicine, Division of Medical Oncology, United States.
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An mTOR feedback loop mediates the 'flare' ('rebound') response to MET tyrosine kinase inhibition. Sci Rep 2023; 13:1378. [PMID: 36697438 PMCID: PMC9876934 DOI: 10.1038/s41598-023-28648-3] [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: 11/03/2022] [Accepted: 01/23/2023] [Indexed: 01/26/2023] Open
Abstract
Targeted therapy significantly impairs tumour growth but suffers from limitations, among which the 'flare' ('rebound') effect. Among cancers driven by tyrosine kinase receptors, those relying on alterations of the MET oncogene benefit from treatment by specific inhibitors. Previously, we reported that discontinuation of MET tyrosine kinase receptor inhibition causes 'rebound' activation of the oncogene, with a post-treatment transient hyperphosphorylation phase that culminates into a dramatic increase in cancer cell proliferation. The molecular mechanisms behind the 'MET burst' after treatment cessation are unknown but critically important for patients. Here we identify a positive feedback loop mediated by the AKT/mTOR pathway leading to (a) enhanced MET translation by activating p70S6K and 4EBP1 and (b) MET hyper-phosphorylation by inactivation of the tyrosine-phosphatase PTP1B. The latter effect is due to m-TOR-driven PTP1B phosphorylation of the inhibitory residues Ser50 and Ser378. These data provide in vitro evidence for the use of mTOR inhibitors to prevent the 'flare effect' in MET targeted therapy, with potential applicative ramifications for patient clinical management.
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15
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Molecular and Biological Investigation of Isolated Marine Fungal Metabolites as Anticancer Agents: A Multi-Target Approach. Metabolites 2023; 13:metabo13020162. [PMID: 36837781 PMCID: PMC9964656 DOI: 10.3390/metabo13020162] [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: 12/10/2022] [Revised: 01/13/2023] [Accepted: 01/19/2023] [Indexed: 01/25/2023] Open
Abstract
Cancer is the leading cause of death globally, with an increasing number of cases being annually reported. Nature-derived metabolites have been widely studied for their potential programmed necrosis, cytotoxicity, and anti-proliferation leading to enrichment for the modern medicine, particularly within the last couple of decades. At a more rapid pace, the concept of multi-target agents has evolved from being an innovative approach into a regular drug development procedure for hampering the multi-fashioned pathophysiology and high-resistance nature of cancer cells. With the advent of the Red Sea Penicillium chrysogenum strain S003-isolated indole-based alkaloids, we thoroughly investigated the molecular aspects for three major metabolites: meleagrin (MEL), roquefortine C (ROC), and isoroquefortine C (ISO) against three cancer-associated biological targets Cdc-25A, PTP-1B, and c-Met kinase. The study presented, for the first time, the detailed molecular insights and near-physiological affinity for these marine indole alkaloids against the assign targets through molecular docking-coupled all-atom dynamic simulation analysis. Findings highlighted the superiority of MEL's binding affinity/stability being quite in concordance with the in vitro anticancer activity profile conducted via sulforhodamine B bioassay on different cancerous cell lines reaching down to low micromolar or even nanomolar potencies. The advent of lengthy structural topologies via the metabolites' extended tetracyclic cores and aromatic imidazole arm permitted multi-pocket accommodation addressing the selectivity concerns. Additionally, the presence decorating polar functionalities on the core hydrophobic tetracyclic ring contributed compound's pharmacodynamic preferentiality. Introducing ionizable functionality with more lipophilic characters was highlighted to improve binding affinities which was also in concordance with the conducted drug-likeness/pharmacokinetic profiling for obtaining a balanced pharmacokinetic/dynamic profile. Our study adds to the knowledge regarding drug development and optimization of marine-isolated indole-based alkaloids for future iterative synthesis and pre-clinical investigations as multi-target anticancer agents.
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Oh KS, Mahalingam M. Melanoma and Glioblastoma-Not a Serendipitous Association. Adv Anat Pathol 2023; 30:00125480-990000000-00051. [PMID: 36624550 DOI: 10.1097/pap.0000000000000393] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Recently, we came across a patient with malignant melanoma and primary glioblastoma. Given this, we parsed the literature to ascertain the relationship, if any, between these 2 malignancies. We begin with a brief overview of melanoma and glioma in isolation followed by a chronologic overview of case reports and epidemiologic studies documenting both neoplasms. This is followed by studies detailing genetic abnormalities common to both malignancies with a view to identifying unifying genetic targets for therapeutic strategies as well as to explore the possibility of a putative association and an inherited cancer susceptibility trait. From a scientific perspective, we believe we have provided evidence favoring an association between melanoma and glioma. Future studies that include documentation of additional cases, as well as a detailed molecular analyses, will lend credence to our hypothesis that the co-occurrence of these 2 conditions is likely not serendipitous.
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Affiliation(s)
- Kei Shing Oh
- Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL
| | - Meera Mahalingam
- Dermatopathology Section, Department of Pathology and Laboratory Medicine, VA-Integrated-Service-Network-1 (VISN1), West Roxbury, MA
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17
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Zheng C, Wang H, Zhao S, Ma C, Gao H, Yang F, Zhou X, Lu J, Zhang C, Zhu H. Inhibition of neuropilin-1 enhances the therapeutic effects of lenvatinib in suppressing cholangiocarcinoma cells via the c-Met pathway. Eur J Pharmacol 2022; 935:175290. [DOI: 10.1016/j.ejphar.2022.175290] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2022] [Revised: 09/11/2022] [Accepted: 09/13/2022] [Indexed: 11/28/2022]
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Xu L, Wang F, Luo F. MET-targeted therapies for the treatment of non-small-cell lung cancer: A systematic review and meta-analysis. Front Oncol 2022; 12:1013299. [PMID: 36387098 PMCID: PMC9646943 DOI: 10.3389/fonc.2022.1013299] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Accepted: 10/17/2022] [Indexed: 08/27/2023] Open
Abstract
BACKGROUND Dysregulation of the mesenchymal epithelial transition (MET) pathway contributes to poor clinical outcomes in patients with non-small cell lung cancer (NSCLC). Numerous clinical trials are currently investigating several therapies based on modulation of the MET pathway. OBJECTIVES This study aimed to systematically evaluate the activity and safety of MET inhibitors in patients with NSCLC. METHODS We searched PubMed, Embase, and the Cochrane Library from inception to June 02, 2022. The objective response rate (ORR) and disease control rate (DCR) were extracted as the main outcomes and pooled using the weighted mean proportion with fixed- or random-effects models in cases of significant heterogeneity (I 2>50%). Safety analysis was performed based on adverse events reported in all studies. RESULTS Eleven studies (882 patients) were included in the meta-analysis. The pooled ORR was 28.1% (95% confidence interval [CI], 0.223-0.354), while the pooled DCR was 69.1% (95% CI, 0.631-0.756). ORRs were higher for tepotinib (44.7% [95% CI, 0.365-0.530]) and savolitinib (42.9% [95% CI, 0.311-0.553]) than for other types of MET inhibitors. Patients with NSCLC with exon 14 skipping exhibited higher ORRs (39.3% (95% CI, 0.296-0.522)) and DCRs (77.8% (95% CI, 0.714-0.847)) than those with MET protein overexpression or amplification. Intracranial response rate and intracranial disease control rates were 40.1% (95% CI, 0.289-0.556) and 95.4% (95% CI, 0.892-0.100), respectively. Adverse events were mild (grade 1 to 2) in 87.2% of patients. Common adverse events above grade 3 included lower extremity edema (3.5% [95% CI, 0.027-0.044]), alanine aminotransferase (ALT) elevation (2.4% [95% CI, 0.014-0.033]), and lipase elevation (2.2% [95% CI, 0.016-0.031]). CONCLUSION MET inhibitors, which exhibited a satisfactory safety profile in the current study, may become a new standard of care for addressing MET dysregulation in patients with advanced or metastatic NSCLC, and even in those with brain metastases, particularly tepotinib, savolitinib and capmatinib. Further randomized trials are required to establish standard predictive biomarkers for MET therapies and to compare the effects of different MET inhibitors in NSCLC with MET dysregulation.
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Affiliation(s)
- Linrui Xu
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Faping Wang
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Fengming Luo
- Department of Pulmonary and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Laboratory of Pulmonary Immunology and Inflammation, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, China
- Clinical Research Center for Respiratory Disease, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Czogalla B, Dötzer K, Sigrüner N, von Koch FE, Brambs CE, Anthuber S, Frangini S, Burges A, Werner J, Mahner S, Mayer B. Combined Expression of HGFR with Her2/neu, EGFR, IGF1R, Mucin-1 and Integrin α2β1 Is Associated with Aggressive Epithelial Ovarian Cancer. Biomedicines 2022; 10:2694. [PMID: 36359213 PMCID: PMC9687566 DOI: 10.3390/biomedicines10112694] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 10/15/2022] [Accepted: 10/21/2022] [Indexed: 09/10/2023] Open
Abstract
Hepatocyte growth factor receptor (HGFR), also known as c-mesenchymal-epithelial transition factor (c-MET), plays a crucial role in the carcinogenesis of epithelial ovarian cancer (EOC). In contrast, the mechanisms contributing to aberrant expression of HGFR in EOC are not fully understood. In the present study, the expression of HGFR with its prognostic and predictive role was evaluated immunohistochemically in a cohort of 42 primary ovarian cancer patients. Furthermore, we analyzed the dual expression of HGFR and other druggable biomarkers. In the multivariate Cox regression analysis, high HGFR expression was identified as an independent prognostic factor for a shorter progression-free survival (PFS) (hazard ratio (HR) 2.99, 95% confidence interval (CI95%) 1.01-8.91, p = 0.049) and overall survival (OS) (HR 5.77, CI95% 1.56-21.34, p = 0.009). In addition, the combined expression of HGFR, human epidermal growth factor receptor 2 (Her2/neu), epithelial growth factor receptor (EGFR), insulin-like growth factor 1 (IGF1R), Mucin-1 and Integrin α2β1 further significantly impaired PFS, platinum-free interval (PFI) and OS. Protein co-expression analyses were confirmed by transcriptomic data in a large, independent cohort of patients. In conclusion, new biomarker-directed treatment targets were identified to fight poor prognosis of primary EOC.
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Affiliation(s)
- Bastian Czogalla
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Katharina Dötzer
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Nicole Sigrüner
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Franz Edler von Koch
- Gynecology and Obstetrics Clinic, Klinikum Dritter Orden, Menzinger Straße 44, 80638 Munich, Germany
| | - Christine E. Brambs
- Department of Obstetrics and Gynecology, Klinikum Rechts der Isar, Technical University Munich, Ismaninger Straße 22, 81675 Munich, Germany
| | - Sabine Anthuber
- Department of Obstetrics and Gynecology, Starnberg Hospital, Oßwaldstraße 1, 82319 Starnberg, Germany
| | - Sergio Frangini
- Department of Obstetrics and Gynecology, Munich Clinic Harlaching, Sanatoriumsplatz 2, 81545 Munich, Germany
| | - Alexander Burges
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Jens Werner
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
| | - Sven Mahner
- Department of Obstetrics and Gynecology, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
| | - Barbara Mayer
- German Cancer Consortium (DKTK), Partner Site Munich, Pettenkoferstraße 8a, 80336 Munich, Germany
- Department of General, Visceral and Transplant Surgery, University Hospital, Ludwig-Maximilians-University Munich, Marchioninistraße 15, 81377 Munich, Germany
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Hepatocyte Growth Factor Enhances Antineoplastic Effect of 5-Fluorouracil by Increasing UPP1 Expression in HepG2 Cells. Int J Mol Sci 2022; 23:ijms23169108. [PMID: 36012373 PMCID: PMC9409026 DOI: 10.3390/ijms23169108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/10/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Aberrant activation of hepatocyte growth factor (HGF) and its receptor c-Met axis promotes tumor growth. Therefore, many clinical trials have been conducted. A phase 3 trial investigating a monoclonal antibody targeting HGF in combination with fluoropyrimidine-based chemotherapy had to be terminated prematurely; however, the reason behind the failure remains poorly defined. In this study, we investigated the influence of HGF on the antineoplastic effects of 5-fluorouracil (5-FU), a fluoropyrimidine, in HepG2 cells. HGF suppressed the proliferative activity of cells concomitantly treated with 5-FU more robustly as compared to that of cells treated with 5-FU alone, and markedly increased the expression of uridine phosphorylase 1 (UPP1). Intracellular concentration of 5-fluorouridine, an initial anabolite of 5-FU catalyzed by UPP1, was increased by HGF. Interestingly, erlotinib enhanced HGF-induced increase in UPP1 mRNA; in contrast, gefitinib suppressed it. Furthermore, erlotinib suppressed HGF-increased phosphorylation of the epidermal growth factor receptor at the Tyr1173 site involved in downregulation of extracellular signal-regulated kinase (Erk) activation, and enhanced the HGF-increased phosphorylation of Erk. Collectively, these findings suggest that inhibition of the HGF/c-Met axis diminishes the effects of fluoropyrimidine through downregulation of UPP1 expression. Therefore, extreme caution must be exercised in terms of patient safety while offering chemotherapy comprising fluoropyrimidine concomitantly with inhibitors of the HGF/c-Met axis.
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21
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Sun H, Zheng J, Xiao J, Yue J, Shi Z, Xuan Z, Chen C, Zhao Y, Tang W, Ye S, Li J, Deng Q, Zhang L, Zhu F, Shao C. TOPK/PBK is phosphorylated by ERK2 at serine 32, promotes tumorigenesis and is involved in sorafenib resistance in RCC. Cell Death Dis 2022; 13:450. [PMID: 35546143 PMCID: PMC9095598 DOI: 10.1038/s41419-022-04909-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2021] [Revised: 04/18/2022] [Accepted: 05/03/2022] [Indexed: 12/14/2022]
Abstract
TOPK/PBK (T-LAK Cell-Originated Protein Kinase) is a serine/threonine kinase that is highly expressed in a variety of human tumors and is associated with poor prognosis in many types of human malignancies. Its activation mechanism is not yet fully understood. A bidirectional signal transduced between TOPK and ERK2 (extracellular signal-regulated kinase 2) has been reported, with ERK2 able to phosphorylate TOPK at the Thr9 residue. However, mutated TOPK at Thr9 cannot repress cellular transformation. In the present study, Ser32 was revealed to be a novel phosphorylated site on TOPK that could be activated by ERK2. Phospho-TOPK (S32) was found to be involved in the resistance of renal cell carcinoma (RCC) to sorafenib. Herein, combined a TOPK inhibitor with sorafenib could promoted the apoptosis of sorafenib-resistant RCC. High expression of HGF/c-met contributes to activation of p-TOPK (S32) during the development of sorafenib resistance in RCC. The current research presents a possible mechanism of sorafenib resistance in RCC and identifies a potential diagnostic marker for predicting sorafenib resistance in RCC, providing a valuable supplement for the clinically targeted treatment of advanced RCC.
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Affiliation(s)
- Huimin Sun
- Central Laboratory, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
- The Key Laboratory for Endocrine-Related Cancer precision Medicine of Xiamen, Xiamen, 361102, Fujian, China
| | - Jianzhong Zheng
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Juanjuan Xiao
- Cancer Research Institute, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China
- Guangxi Health Commission Key Laboratory of Novel Onco-Kinases in Target Therapy, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China
| | - Juntao Yue
- Department of Urology, 985th hospital of PLA, Taiyuan, 030002, Shanxi, China
| | - Zhiyuan Shi
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Zuodong Xuan
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Chen Chen
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Yue Zhao
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Wenbin Tang
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Shaopei Ye
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Jinxin Li
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China
| | - Qiumin Deng
- The Key Laboratory for Endocrine-Related Cancer precision Medicine of Xiamen, Xiamen, 361102, Fujian, China
- School of Medicine, Xiamen University, Xiamen, 361102, Fujian, China
| | - Lei Zhang
- Department of Public healthy, Xiamen University, Xiamen, 361102, Fujian, China
| | - Feng Zhu
- Cancer Research Institute, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
- Guangxi Health Commission Key Laboratory of Novel Onco-Kinases in Target Therapy, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, the Affiliated Hospital of Guilin Medical University, Guilin, 541001, Guangxi, China.
| | - Chen Shao
- Department of Urology, Xiang'an Hospital of Xiamen University, Xiamen, 361102, Fujian, China.
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Chen S, Xu Z, Li S, Liang H, Zhang C, Wang Z, Li J, Li J, Yang H. Systematic Interrogation of Cellular Signaling in Live Cells Using a Membrane‐Anchored DNA Multitasking Processor. Angew Chem Int Ed Engl 2022; 61:e202113795. [DOI: 10.1002/anie.202113795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Indexed: 12/11/2022]
Affiliation(s)
- Shan Chen
- Fujian Key Laboratory of Functional Marine Sensing Materials Fuzhou Institute of Oceanography Minjiang University Fuzhou 350108 P.R. China
- MOE Key Laboratory for Analytical Science of Food Safety and Biology Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry Fuzhou University Fuzhou 350108 P.R. China
| | - Zhifei Xu
- MOE Key Laboratory for Analytical Science of Food Safety and Biology Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry Fuzhou University Fuzhou 350108 P.R. China
| | - Shiwei Li
- MOE Key Laboratory for Analytical Science of Food Safety and Biology Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry Fuzhou University Fuzhou 350108 P.R. China
| | - Hong Liang
- Fujian Key Laboratory of Functional Marine Sensing Materials Fuzhou Institute of Oceanography Minjiang University Fuzhou 350108 P.R. China
| | - Chen Zhang
- Fujian Key Laboratory of Functional Marine Sensing Materials Fuzhou Institute of Oceanography Minjiang University Fuzhou 350108 P.R. China
| | - Zonghua Wang
- Fujian Key Laboratory of Functional Marine Sensing Materials Fuzhou Institute of Oceanography Minjiang University Fuzhou 350108 P.R. China
| | - Jingying Li
- MOE Key Laboratory for Analytical Science of Food Safety and Biology Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry Fuzhou University Fuzhou 350108 P.R. China
- College of Biological Science and Engineering Fuzhou University Fuzhou 350108 P.R. China
| | - Juan Li
- MOE Key Laboratory for Analytical Science of Food Safety and Biology Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry Fuzhou University Fuzhou 350108 P.R. China
| | - Huanghao Yang
- MOE Key Laboratory for Analytical Science of Food Safety and Biology Fujian Provincial Key Laboratory of Analysis and Detection Technology for Food Safety State Key Laboratory of Photocatalysis on Energy and Environment College of Chemistry Fuzhou University Fuzhou 350108 P.R. China
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To KKW, Cho WCS. Mesenchymal Epithelial Transition Factor (MET): A Key Player in Chemotherapy Resistance and an Emerging Target for Potentiating Cancer Immunotherapy. Curr Cancer Drug Targets 2022; 22:269-285. [PMID: 35255791 DOI: 10.2174/1568009622666220307105107] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/10/2021] [Accepted: 01/10/2022] [Indexed: 11/22/2022]
Abstract
The MET protein is a cell surface receptor tyrosine kinase predominately expressed in epithelial cells. Upon binding of its only known ligand, hepatocyte growth factor (HGF), MET homodimerizes, phosphorylates, and stimulates intracellular signalling to drive cell proliferation. Amplification or hyperactivation of MET is frequently observed in various cancer types and it is associated with poor response to conventional and targeted chemotherapy. More recently, emerging evidence also suggests that MET/HGF signalling may play an immunosuppressive role and it could confer resistance to cancer immunotherapy. In this review, we summarized the preclinical and clinical evidence of MET's role in drug resistance to conventional chemotherapy, targeted therapy, and immunotherapy. Previous clinical trials investigating MET-targeted therapy in unselected or MET-overexpressing cancers yielded mostly unfavourable results. More recent clinical studies focusing on MET exon 14 alterations and MET amplification have produced encouraging treatment responses to MET inhibitor therapy. The translational relevance of MET inhibitor therapy to overcome drug resistance in cancer patients is discussed.
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Affiliation(s)
- Kenneth K W To
- School of Pharmacy, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - William C S Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Hong Kong SAR, China
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He T, Gao Y, Fang Y, Zhang Y, Zhang S, Nan F, Ding J, Chen Y. The HDAC inhibitor GCJ-490A suppresses c-Met expression through IKKα and overcomes gefitinib resistance in non-small cell lung cancer. Cancer Biol Med 2022; 19:j.issn.2095-3941.2021.0130. [PMID: 35188360 PMCID: PMC9425179 DOI: 10.20892/j.issn.2095-3941.2021.0130] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
Objective: The novel compound GCJ-490A has been discovered as a pan-histone deacetylase (HDAC) inhibitor that exerts potent inhibitory activity against HDAC1, HDAC3, and HDAC6. Because of the important roles of HDACs in lung cancer development and the high distribution of GCJ-490A in lung tissue, we explored the anti-tumor potency of GCJ-490A against non-small cell lung cancer (NSCLC) in vitro and in vivo in this study. Methods: The in vitro effects of GCJ-490A alone or combined with the EGFR inhibitor gefitinib against NSCLC were measured with proliferation, apoptosis, and colony formation assays. NSCLC xenograft models were used to investigate the efficacy of GCJ-490A combined with gefitinib for the treatment of NSCLC in vivo. Western blot assays, luciferase reporter assays, chromatin immunoprecipitation assays, quantitative real time-PCR, immunohistochemistry, and transcription factor activity assays were used to elucidate possible mechanisms. Results: GCJ-490A effectively inhibited NSCLC cell proliferation and induced apoptosis in vitro and in vivo. Interestingly, inhibition of HDAC1 and HDAC6 by GCJ-490A increased histone acetylation at the IKKα promoter and enhanced IKKα transcription, thus decreasing c-Met. Moreover, this c-Met downregulation was found to be essential for the synergistic anti-tumor activity of GCJ-490A and gefitinib. Conclusions: These findings highlight the promising potential of HDAC inhibitors in NSCLC treatment and provide a rational basis for the application of HDAC inhibitors in combination with EGFR inhibitors in clinical trials.
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Affiliation(s)
- Ting He
- Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yinglei Gao
- Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yanfen Fang
- Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yangming Zhang
- State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Shuwei Zhang
- University of Chinese Academy of Sciences, Beijing 100049, China.,State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Fajun Nan
- State Key Laboratory of Drug Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jian Ding
- Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yi Chen
- Division of Anti-Tumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.,University of Chinese Academy of Sciences, Beijing 100049, China
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25
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Xu X, Jiang W, Han P, Zhang J, Tong L, Sun X. MicroRNA-128-3p Mediates Lenvatinib Resistance of Hepatocellular Carcinoma Cells by Downregulating c-Met. J Hepatocell Carcinoma 2022; 9:113-126. [PMID: 35252056 PMCID: PMC8894104 DOI: 10.2147/jhc.s349369] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 02/12/2022] [Indexed: 01/20/2023] Open
Abstract
Objective Lenvatinib is a first-line multikinase inhibitor for advanced hepatocellular carcinoma (HCC), but resistance to the drug remains a major hurdle for its long-term anti-cancer activity. This resistance is thought to be due to overexpression of c-Met. This study aims to identify potential upstream microRNAs (miRNAs) that regulate c-Met, investigate the underlying mechanisms, and seek potential strategies that may reverse such resistance. Methods Lenvatinib-resistant HCC (LR-HCC) cells were established from human HCC Huh7 and SMMC-7721 cells. Assays of cell proliferation, cell cycle distribution, apoptosis, RT-qPCR, Western blot analysis and immunohistochemistry were employed. Potential miRNAs were screened by miRNA-target prediction tools and their regulatory effects were evaluated by luciferase reporter assays. Xenograft tumor models were used to evaluate the therapeutic effects. Results LR-HCC cells were refractory to lenvatinib-induced growth inhibition and apoptosis in vitro and in vivo. Sustained exposure of cells to lenvatinib resulted in increased expression and phosphorylation of c-Met, and c-Met inhibition enhanced the effects of lenvatinib in suppressing LR-HCC cells. Among eleven miRNA candidates, miR-128-3p displayed the most vigorous activity to negatively regulate c-Met and was downregulated in LR-HCC cells. MiR-128-3p mimics inhibited proliferation and induced apoptosis of LR-HCC cells, and enhanced the effects of lenvatinib in cell culture and animal models. MiR-128-3p and c-Met participate in the mechanisms underlying lenvatinib resistance through regulating Akt that mediates the apoptotic pathway and ERK (extracellular-signal-regulated kinase) modulating cell cycle progression. Conclusion The present results indicate that the miR-128-3p/c-Met axis may be potential therapeutic targets for circumventing lenvatinib resistance in HCC and warrant further investigation.
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Affiliation(s)
- Xin Xu
- Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China
- Department of General Surgery, Daqing Oil Field General Hospital, Daqing, 163000, People’s Republic of China
| | - Wenjing Jiang
- Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China
| | - Peng Han
- Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China
| | - Jingyan Zhang
- Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, 163316, People’s Republic of China
| | - Liquan Tong
- Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, 163316, People’s Republic of China
- Liquan Tong, Department of General Surgery, The Fifth Affiliated Hospital of Harbin Medical University, Daqing, 163316, People’s Republic of China, Email
| | - Xueying Sun
- Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China
- Correspondence: Xueying Sun, Hepatosplenic Surgery Center, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, People’s Republic of China, Email
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Chen S, Xu Z, Li S, Liang H, Zhang C, Wang Z, Li J, Li J, Yang H. Systematic Interrogation of Cellular Signaling in Live Cells using a Membrane‐anchored DNA Multitasking Processor. Angew Chem Int Ed Engl 2022. [DOI: 10.1002/ange.202113795] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Shan Chen
- Minjiang University Fujian Key Laboratory of Functional Marine Sensing Materials, Fuzhou Institute of Oceanography CHINA
| | - Zhifei Xu
- Fuzhou University College of Chemistry CHINA
| | - Shiwei Li
- Fuzhou University College of Chemistry CHINA
| | - Hong Liang
- Minjiang University Fujian Key Laboratory of Functional Marine Sensing Materials, Fuzhou Institute of Oceanography CHINA
| | - Chen Zhang
- Minjiang University Fujian Key Laboratory of Functional Sensing Materials, Fuzhou Institute of Oceanography CHINA
| | - Zonghua Wang
- Minjiang University Fujian Key Laboratory of Functional Sensing Materials, Fuzhou Institute of Oceanography CHINA
| | - Jingying Li
- Fuzhou University College of Biological Science and Engineering Qi Shan Campus of Fuzhou University,2 Xue Yuan Road 350108 Fuzhou CHINA
| | - Juan Li
- Fuzhou University College of Chemistry CHINA
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27
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Yassin NYS, AbouZid SF, El-Kalaawy AM, Ali TM, Almehmadi MM, Ahmed OM. Silybum marianum total extract, silymarin and silibinin abate hepatocarcinogenesis and hepatocellular carcinoma growth via modulation of the HGF/c-Met, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. Biomed Pharmacother 2022; 145:112409. [PMID: 34781148 DOI: 10.1016/j.biopha.2021.112409] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has been identified as one of the most deadly malignancies with limited therapeutic efficacy worldwide. However, understanding the molecular mechanisms of crosstalk between signaling pathways in HCC and predicting cancer cell responses to targeted therapeutic interventions remain to be challenge. Thus, in this study, we aimed to evaluate the anticancerous efficacy of Silybum marianum total extract (STE), silymarin (Sm), and silibinin (Sb) against experimentally-induced HCC in rats. In vitro investigations were also performed and the anticancer effects against HCC cell lines (HepG2 and Huh7) were confirmed. Wistar rats were given diethylnitrosamine (DEN)/2-acetylaminofluorene (AAF)/carbon tetrachloride (CCl4) and were orally treated with STE (200 mg/kg body weight (bw)), Sm (150 mg/kg bw), and Sb (5 mg/kg bw) every other day from the 1st or 16th week to the 25th week of DEN/AAF/CCl4 injection. Treatment with STE, Sm, and Sb inhibited the growth of cancerous lesions in DEN/AAF/CCl4-treated rats. This inhibition was associated with inhibition of Ki-67 expression and repression of HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR signaling pathways. STE, Sm, and Sb improved liver function biomarkers and tumor markers (AFP, CEA, and CA19.9) and increased total protein and albumin levels in serum. STE, Sm, and Sb treatment was also noted to reduce the hepatic production of lipid peroxides, increase hepatic glutathione content, and induce the activities of hepatic antioxidant enzymes in DEN/AAF/CCl4-treated rats. These results indicate that STE, Sm, and Sb exert anti-HCC effects through multiple pathways, including suppression of Ki-67 expression and HGF/cMet, Wnt/β-catenin, and PI3K/Akt/mTOR pathways and enhancement of antioxidant defense mechanisms.
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Affiliation(s)
- Nour Y S Yassin
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt
| | - Sameh F AbouZid
- Department of Pharmacognosy, Faculty of Pharmacy, Heliopolis University for Sustainable Development, 3 Cairo-Belbeis Desert Road, P.O. Box 3020 El Salam, 11785 Cairo, Egypt
| | - Asmaa M El-Kalaawy
- Department of Pharmacology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt
| | - Tarek M Ali
- Department of Physiology, College of Medicine, Taif University, P. O. Box 11099, Taif 21944, Saudi Arabia
| | - Mazen M Almehmadi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, P. O. Box 11099, Taif 21944, Saudi Arabia
| | - Osama M Ahmed
- Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt.
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Pathak N, Chitikela S, Malik PS. Recent advances in lung cancer genomics: Application in targeted therapy. ADVANCES IN GENETICS 2021; 108:201-275. [PMID: 34844713 DOI: 10.1016/bs.adgen.2021.08.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Genomic characterization of lung cancer has not only improved our understanding of disease biology and carcinogenesis but also revealed several therapeutic opportunities. Targeting tumor dependencies on specific genomic alterations (oncogene addiction) has accelerated the therapeutic developments and significantly improved the outcomes even in advanced stage of disease. Identification of genomic alterations predicting response to specific targeted treatment is the key to success for this "personalized treatment" approach. Availability of multiple choices of therapeutic options for specific genomic alterations highlight the importance of optimum sequencing of drugs. Multiplex gene testing has become mandatory in view of constantly increasing number of therapeutic targets and effective treatment options. Influence of genomic characteristics on response to immunotherapy further makes comprehensive genomic profiling necessary before therapeutic decision making. A comprehensive elucidation of resistance mechanisms and directed treatments have made the continuum of care possible and transformed this deadly disease into a chronic condition. Liquid biopsy-based approach has made the dynamic monitoring of disease possible and enabled treatment optimizations accordingly. Current lung cancer management is the perfect example of "precision-medicine" in clinical oncology.
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Affiliation(s)
- Neha Pathak
- Department of Medical Oncology, Dr. B.R.A.I.R.C.H., All India Institute of Medical Sciences, New Delhi, India
| | - Sindhura Chitikela
- Department of Medical Oncology, Dr. B.R.A.I.R.C.H., All India Institute of Medical Sciences, New Delhi, India
| | - Prabhat Singh Malik
- Department of Medical Oncology, Dr. B.R.A.I.R.C.H., All India Institute of Medical Sciences, New Delhi, India.
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Zhao S, Wu W, Jiang H, Ma L, Pan C, Jin C, Mo J, Wang L, Wang K. Selective Inhibitor of the c-Met Receptor Tyrosine Kinase in Advanced Hepatocellular Carcinoma: No Beneficial Effect With the Use of Tivantinib? Front Immunol 2021; 12:731527. [PMID: 34804015 PMCID: PMC8600564 DOI: 10.3389/fimmu.2021.731527] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 10/18/2021] [Indexed: 12/12/2022] Open
Abstract
Advanced hepatocellular carcinoma (HCC) remains a formidable health challenge worldwide, with a 5-year survival rate of 2.4% in patients with distant metastases. The hepatocyte growth factor/cellular-mesenchymal-epithelial transition (HGF/c-Met) signaling pathway represents an encouraging therapeutic target for progressive HCC. Tivantinib, a non-adenosine triphosphate-competitive c-Met inhibitor, showed an attractive therapeutic effect on advanced HCC patients with high MET-expression in phase 2 study but failed to meet its primary endpoint of prolonging the overall survival (OS) in two phase 3 HCC clinical trials. Seven clinical trials have been registered in the "ClinicalTrials.gov" for investigating the safety and efficacy of tivantinib in treating advanced or unresectable HCC. Eight relevant studies have been published with results. The sample size ranged from 20 to 340 patients. The methods of tivantinib administration and dosage were orally 120/240/360 mg twice daily. MET overexpression was recorded at 34.6% to 100%. Two large sample phase 3 studies (the METIV-HCC study of Australia and European population and the JET-HCC study of the Japanese population) revealed that tivantinib failed to show survival benefits in advanced HCC. Common adverse events with tivantinib treatment include neutropenia, ascites, rash, and anemia, etc. Several factors may contribute to the inconsistency between the phase 2 and phase 3 studies of tivantinib, including the sample size, drug dosing, study design, and the rate of MET-High. In the future, high selective MET inhibitors combined with a biomarker-driven patient selection may provide a potentially viable therapeutic strategy for patients with advanced HCC.
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Affiliation(s)
- Shankun Zhao
- Department of Urology, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Weizhou Wu
- Department of Urology, Maoming People's Hospital, Maoming, China
| | - Hao Jiang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Lei Ma
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chengyi Pan
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Chong Jin
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Jinggang Mo
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Liezhi Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
| | - Kunpeng Wang
- Department of General Surgery, Taizhou Central Hospital (Taizhou University Hospital), Taizhou, China
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Sun Z, Yin S, Zhao C, Fan LH, Hu H. Involvement of PD-L1-mediated Tumor Intrinsic Signaling and Immune Suppression in Tumorigenic Effect of α-Tocopherol. Carcinogenesis 2021; 43:243-253. [PMID: 34657155 DOI: 10.1093/carcin/bgab096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 10/12/2021] [Accepted: 10/14/2021] [Indexed: 11/13/2022] Open
Abstract
Numerous studies have shown that the different isoforms vitamin E have distinct activity on carcinogenesis. α-Tocopherol (α-T), the most abundant vitamin E in certain types of food and animal tissues, has demonstrated a cancer-promoting effect in a number of human clinical trials and pre-clinical studies, whereas the γ- and δ- forms of Tocopherols and Tocotrienols have exhibited significant anticancer effect in various pre-clinical studies. However, the mechanisms underlying the tumorigenic effect of α-T have not yet been fully understood. In the present study, we found that α-T was able to activate Programmed death-ligand 1 (PD-L1)-mediated tumor-intrinsic signaling and immune suppression via JAK/STAT3-dependent transcriptional and ERK-dependent posttranscriptional mechanism. In line with PD-L1 induction, α-T treatment increased cancer cell viability in vitro and promoted tumor growth in LLC xenograft mouse model. The findings of the present study for the first time provided evidence that PD-L1-mediated tumor-intrinsic and immune escape mechanism contributed to the tumorigenic effect of α-T.
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Affiliation(s)
- Zhenou Sun
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, Haidian District, Beijing, China
| | - Shutao Yin
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, Haidian District, Beijing, China
| | - Chong Zhao
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, Haidian District, Beijing, China
| | - Li Hong Fan
- College of Veterinary Medicine, China Agricultural University, Haidian District, Beijing, China
| | - Hongbo Hu
- College of Food Science and Nutritional Engineering, Beijing Key Laboratory for Food Non-thermal Processing, China Agricultural University, Haidian District, Beijing, China
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Laxmikeshav K, Kumari P, Shankaraiah N. Expedition of sulfur-containing heterocyclic derivatives as cytotoxic agents in medicinal chemistry: A decade update. Med Res Rev 2021; 42:513-575. [PMID: 34453452 DOI: 10.1002/med.21852] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 04/20/2021] [Accepted: 08/17/2021] [Indexed: 12/13/2022]
Abstract
This review article proposes a comprehensive report of the design strategies engaged in the development of various sulfur-bearing cytotoxic agents. The outcomes of various studies depict that the sulfur heterocyclic framework is a fundamental structure in diverse synthetic analogs representing a myriad scope of therapeutic activities. A number of five-, six- and seven-membered sulfur-containing heterocyclic scaffolds, such as thiazoles, thiadiazoles, thiazolidinediones, thiophenes, thiopyrans, benzothiazoles, benzothiophenes, thienopyrimidines, simple and modified phenothiazines, and thiazepines have been discussed. The subsequent studies of the derivatives unveiled their cytotoxic effects through multiple mechanisms (viz. inhibition of tyrosine kinases, topoisomerase I and II, tubulin, COX, DNA synthesis, and PI3K/Akt and Raf/MEK/ERK signaling pathways), and several others. Thus, our concise illustration explains the design strategy and anticancer potential of these five- and six-membered sulfur-containing heterocyclic molecules along with a brief outline on seven-membered sulfur heterocycles. The thorough assessment of antiproliferative activities with the reference drug allows a proficient assessment of the structure-activity relationships (SARs) of the diversely synthesized molecules of the series.
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Affiliation(s)
- Kritika Laxmikeshav
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Pooja Kumari
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
| | - Nagula Shankaraiah
- Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Hyderabad, India
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Collard M, Gallagher PE, Tallant EA. A Polyphenol-Rich Extract From Muscadine Grapes Inhibits Triple-Negative Breast Tumor Growth. Integr Cancer Ther 2021; 19:1534735420917444. [PMID: 32578460 PMCID: PMC7315667 DOI: 10.1177/1534735420917444] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that tends to affect young women and has a high propensity to metastasize. No targeted treatments are available for this type of breast cancer due to a lack of estrogen or progesterone receptors or overexpression of human epidermal growth factor receptor type 2 overexpression. Currently, patients have no therapeutic options once standard of care is complete, indicating a need for safe and effective therapies to slow or prevent the progression of TNBC to metastatic disease. Studies showed that isolated polyphenols or polyphenol-rich muscadine grape extracts polyphenols inhibit the proliferation of various cancer cells including breast cancer. A proprietary muscadine grape extract (MGE) was administered to nude mice with human MDA-MB-231 TNBC atumors for 4 weeks to determine the effect of the extract on tumor growth. MGE decreased tumor volume in association with a reduction in the proliferative markers Ki67 and cyclin D1. To determine the molecular mechanisms for the MGE-induced reduction in tumor growth, mouse 4T1, MDA-MB-231, or human BT-549 TNBC cells were treated with MGE, and various signaling pathways were investigated. MGE reduced c-Met, differentially abrogated ERK/MAPK and AKT signaling, and decreased a downstream targets of ERK/MAPK and AKT pathways, cyclin D1. Cyclin D1 reduction was associated with retinoblastoma activation and cell cycle arrest in MDA-MB-231 TNBC cells. MGE-regulated molecular signaling pathways were functionally associated with a dose-dependent reduction in cell proliferation. The pluripotency of MGE and high index of safety and tolerability suggest that the extract may serve as a therapeutic to reduce TNBC progression to metastatic disease.
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Affiliation(s)
| | | | - E Ann Tallant
- Wake Forest School of Medicine, Winston-Salem, NC, USA
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Shi T, Hu J, Wang W, Jiang Q, Xu Z, Yu S, Wang F, Liu X. Multiple Blockades of the HGF/Met Signaling Pathway for Metastasis Suppression Using Nanoinhibitors. ACS APPLIED MATERIALS & INTERFACES 2021; 13:30350-30358. [PMID: 34165951 DOI: 10.1021/acsami.1c07010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
The hepatocyte growth factor (HGF)/HGF receptor (Met) signaling pathway serves as a potential target for preventing tumor metastasis yet poorly explored. Here, we developed a Met-targeted nanoinhibitor to efficiently suppress metastasis via a multiple blockading HGF/Met signaling pathway. A biocompatible nanovector comprising multiple type of inhibitors enables interrupting extracellular domain dimerization and intracellular domain phosphorylation simultaneously. Such a comprehensive blockade of signaling pathway restrains unregulated tumor cell migration, invasion, and proliferation and thus remarkably suppresses metastasis in an orthotopic breast tumor model. This method provides a safe and effective option for metastasis inhibition via modulation of the cell signaling pathway. To our best knowledge, the strategy of the multiple blockading signaling pathway has not been reported for preventing tumor metastasis.
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Affiliation(s)
- Tianhui Shi
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Jialing Hu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Wenxiao Wang
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Qunying Jiang
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Zhen Xu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Shuyi Yu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Fuan Wang
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
| | - Xiaoqing Liu
- College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, P. R. China
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Brain-invasive meningiomas: molecular mechanisms and potential therapeutic options. Brain Tumor Pathol 2021; 38:156-172. [PMID: 33903981 DOI: 10.1007/s10014-021-00399-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2021] [Accepted: 04/07/2021] [Indexed: 02/07/2023]
Abstract
Meningiomas are the most commonly diagnosed benign intracranial adult tumors. Subsets of meningiomas that present with extensive invasion into surrounding brain areas have high recurrence rates, resulting in difficulties for complete resection, substantially increased mortality of patients, and are therapeutically challenging for neurosurgeons. Exciting new data have provided insights into the understanding of the molecular machinery of invasion. Moreover, clinical trials for several novel approaches have been launched. Here, we will highlight the mechanisms which govern brain invasion and new promising therapeutic approaches for brain-invasive meningiomas, including pharmacological approaches targeting three major aspects of tumor cell invasion: extracellular matrix degradation, cell adhesion, and growth factors, as well as other innovative treatments such as immunotherapy, hormone therapy, Tumor Treating Fields, and biodegradable copolymers (wafers), impregnated chemotherapy. Those ongoing studies can offer more diversified possibilities of potential treatments for brain-invasive meningiomas, and help to increase the survival benefits for patients.
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Properties of FDA-approved small molecule protein kinase inhibitors: A 2021 update. Pharmacol Res 2021; 165:105463. [DOI: 10.1016/j.phrs.2021.105463] [Citation(s) in RCA: 165] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023]
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Metabolomic Analysis to Elucidate Mechanisms of Sunitinib Resistance in Renal Cell Carcinoma. Metabolites 2020; 11:metabo11010001. [PMID: 33374949 PMCID: PMC7821950 DOI: 10.3390/metabo11010001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/14/2020] [Accepted: 12/18/2020] [Indexed: 02/07/2023] Open
Abstract
Metabolomics analysis possibly identifies new therapeutic targets in treatment resistance by measuring changes in metabolites accompanying cancer progression. We previously conducted a global metabolomics (G-Met) study of renal cell carcinoma (RCC) and identified metabolites that may be involved in sunitinib resistance in RCC. Here, we aimed to elucidate possible mechanisms of sunitinib resistance in RCC through intracellular metabolites. We established sunitinib-resistant and control RCC cell lines from tumor tissues of RCC cell (786-O)-injected mice. We also quantified characteristic metabolites identified in our G-Met study to compare intracellular metabolism between the two cell lines using liquid chromatography-mass spectrometry. The established sunitinib-resistant RCC cell line demonstrated significantly desuppressed protein kinase B (Akt) and mesenchymal-to-epithelial transition (MET) phosphorylation compared with the control RCC cell line under sunitinib exposure. Among identified metabolites, glutamine, glutamic acid, and α-KG (involved in glutamine uptake into the tricarboxylic acid (TCA) cycle for energy metabolism); fructose 6-phosphate, D-sedoheptulose 7-phosphate, and glucose 1-phosphate (involved in increased glycolysis and its intermediate metabolites); and glutathione and myoinositol (antioxidant effects) were significantly increased in the sunitinib-resistant RCC cell line. Particularly, glutamine transporter (SLC1A5) expression was significantly increased in sunitinib-resistant RCC cells compared with control cells. In this study, we demonstrated energy metabolism with glutamine uptake and glycolysis upregulation, as well as antioxidant activity, was also associated with sunitinib resistance in RCC cells.
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Min B, Jin J, Kim H, Her NG, Park C, Kim D, Yang J, Hwang J, Kim E, Choi M, Song HY, Nam DH, Yoon Y. cIRCR201-dPBD, a Novel Pyrrolobenzodiazepine Dimer-Containing Site-Specific Antibody-Drug Conjugate Targeting c-Met Overexpression Tumors. ACS OMEGA 2020; 5:25798-25809. [PMID: 33073104 PMCID: PMC7557224 DOI: 10.1021/acsomega.0c03102] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 09/15/2020] [Indexed: 06/11/2023]
Abstract
c-Met, as a receptor expressed on the cell membrane, contributes to the growth and metastasis of tumors, as well as angiogenesis, mainly through the hepatocyte growth factor (HGF)/c-Met axis during tumor progression. Although several c-Met inhibitors, including small molecules and monoclonal antibody inhibitors, are currently being investigated, their clinical outcomes have not been promising. Development of an antibody-drug conjugate (ADC) against c-Met could be an attractive therapeutic strategy that would provide superior antitumor efficacy with broad-spectrum c-Met expression levels. In the present study, site-specific drug-conjugate technology was applied to develop an ADC using the human-mouse cross-reactive c-Met antibody and a prodrug pyrrolobenzodiazepine (PBD). The toxin payload was uniformly conjugated to the light-chain C-terminus of the native cIRCR201 antibody (drug-to-antibody ratio = 2), as confirmed using LC-MS. Using a high-throughput screening system, we found that cIRCR201-dPBD exhibited varying sensitivities depending on the expression levels of c-Met, and it induced receptor-mediated endocytosis and toxin-mediated apoptosis in 47 different cancer cell lines. cIRCR201-dPBD also showed significant antitumor activity on the MET-amplified cancer cells using in vivo xenograft models. Therefore, cIRCR201-dPBD could be a promising therapeutic strategy for tumors with c-Met expression.
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Affiliation(s)
- Byeongkwi Min
- Department
of Health Sciences and Technology, Samsung Advanced Institute for
Health Sciences and Technology, Sungkyunkwan
University, Seoul 06355, Republic of Korea
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Jonghwa Jin
- Department
of Convergence Technical Support, New Drug
Development Center, 123
Osongsaengmyeng-ro, Cheongju-si, Chungbuk 28160, Korea
| | - Hyeree Kim
- Department
of Health Sciences and Technology, Samsung Advanced Institute for
Health Sciences and Technology, Sungkyunkwan
University, Seoul 06355, Republic of Korea
- Samsung
Biomedical
Research Institute, Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Nam-Gu Her
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Changsik Park
- LegoChem
Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea
| | - Donggeon Kim
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Jehoon Yang
- Animal
Research and Molecular Imaging Center, Samsung
Biomedical Research Institute, Seoul 06351, Republic
of Korea
| | - Juhyeon Hwang
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Eunmi Kim
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
| | - Minji Choi
- LegoChem
Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea
| | - Ho Young Song
- LegoChem
Biosciences, Inc., 8-26 Munoyeongseo-ro, Daedeok-gu, Daejeon, 34302, Republic of Korea
| | - Do-Hyun Nam
- Department
of Health Sciences and Technology, Samsung Advanced Institute for
Health Sciences and Technology, Sungkyunkwan
University, Seoul 06355, Republic of Korea
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
- Department
of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic
of Korea
| | - Yeup Yoon
- Department
of Health Sciences and Technology, Samsung Advanced Institute for
Health Sciences and Technology, Sungkyunkwan
University, Seoul 06355, Republic of Korea
- Institute
for Refractory Cancer Research, Research
Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Republic of Korea
- Research
Institute for Future Medicine, Samsung Medical
Center, Seoul 06351, Republic of Korea
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Silva Paiva R, Gomes I, Casimiro S, Fernandes I, Costa L. c-Met expression in renal cell carcinoma with bone metastases. J Bone Oncol 2020; 25:100315. [PMID: 33024658 PMCID: PMC7527574 DOI: 10.1016/j.jbo.2020.100315] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 08/26/2020] [Accepted: 08/27/2020] [Indexed: 12/12/2022] Open
Abstract
Bone is a common metastatic site in renal cell carcinoma (RCC). HGF/c-Met pathway is particularly relevant in tumors with bone metastases. c-Met/HGF pathway is involved in RCC progression, conferring poor prognosis. Several c-Met targeting therapies are currently in clinical development. c-Met expression is an important therapeutic target in RCC with bone metastases. Hepatocyte growth factor (HGF)/c-Met pathway is implicated in embryogenesis and organ development and differentiation. Germline or somatic mutations, chromosomal rearrangements, gene amplification, and transcriptional upregulation in MET or alterations in autocrine or paracrine c-Met signalling have been associated with cancer cell proliferation and survival, including in renal cell carcinoma (RCC), and associated with disease progression. HGF/c-Met pathway has been shown to be particularly relevant in tumors with bone metastases (BMs). However, the efficacy of targeting c-Met in bone metastatic disease, including in RCC, has not been proven. Therefore, further investigation is required focusing the particular role of HGF/c-Met pathway in bone microenvironment (BME) and how to effectively target this pathway in the context of bone metastatic disease.
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Key Words
- ALK, anaplastic lymphoma kinase gene
- AR, androgen receptor
- ATP, adenosine triphosphate
- AXL, AXL Receptor Tyrosine Kinase
- BME, bone microenvironment
- BMPs, bone morphogenetic proteins
- BMs, bone metastases
- BPs, Bisphosphonates
- BTAs, Bone-targeting agents
- Bone metastases
- CCL20, chemokine (C-C motif) ligand 20
- CI, confidence interval
- CRPC, Castration Resistant Prostate Cancer
- CSC, cancer stem cells
- CTC, circulating tumor cells
- CaSR, calcium/calcium-sensing receptor
- EMA, European Medicines Agency
- EMT, epithelial-to-mesenchymal transition
- FDA, US Food and Drug Administration
- FLT-3, FMS-like tyrosine kinase 3
- GEJ, Gastroesophageal Junction
- HCC, Hepatocellular Carcinoma
- HGF, hepatocyte growth factor
- HGF/c-Met
- HIF, hypoxia-inducible factors
- HR, hazard ratio
- IGF, insulin-like growth factor
- IGF2BP3, insulin mRNA Binding Protein-3
- IL, interleukin
- IRC, independent review committees
- KIT, tyrosine-protein kinase KIT
- Kidney cancer
- M-CSF, macrophage colony-stimulating factor
- MET, MET proto-oncogene, receptor tyrosine kinase
- NSCLC, non-small cell lung carcinoma
- ORR, overall response rate
- OS, overall survival
- PDGF, platelet-derived growth factor
- PFS, progression free survival
- PTHrP, parathyroid hormone-related peptide
- RANKL, receptor activator of nuclear factor-κB ligand
- RCC, renal cell carcinoma
- RET, rearranged during transfection proto-oncogene
- ROS, proto-oncogene tyrosine-protein kinase ROS
- RTK, receptor tyrosine kinase
- SCLC, Squamous Cell Lung Cancer
- SREs, skeletal-related events
- SSE, symptomatic skeletal events
- TGF-β, transforming growth factor-β
- TIE-2, Tyrosine-Protein Kinase Receptor TIE-2
- TKI, tyrosine kinase inhibitor
- TRKB, Tropomyosin receptor kinase B
- Targeted therapy
- VEGFR, vascular endothelial growth factor receptor
- VHL, Hippel-Lindau tumor suppressor gene
- ZA, zoledronic acid
- ccRCC, clear-cell RCC
- mAb, monoclonal antibodies
- pRCC, papillary renal cell carcinoma
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Affiliation(s)
- Rita Silva Paiva
- Oncology Division, Hospital de Santa Maria, CHULN, 1649-035 Lisboa, Portugal
| | - Inês Gomes
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Sandra Casimiro
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Isabel Fernandes
- Oncology Division, Hospital de Santa Maria, CHULN, 1649-035 Lisboa, Portugal
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
| | - Luís Costa
- Oncology Division, Hospital de Santa Maria, CHULN, 1649-035 Lisboa, Portugal
- Instituto de Medicina Molecular - João Lobo Antunes, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal
- Corresponding author at: Oncology Division, Hospital de Santa Maria, 1649-035 Lisbon, Portugal.
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Kumar S, Fayaz F, Pottoo FH, Bajaj S, Manchanda S, Bansal H. Nanophytomedicine Based Novel Therapeutic Strategies in Liver Cancer. Curr Top Med Chem 2020; 20:1999-2024. [DOI: 10.2174/1568026619666191114113048] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 06/25/2020] [Accepted: 06/29/2020] [Indexed: 02/06/2023]
Abstract
Liver cancer is the fifth (6.3% of all cancers i.e., 548,000 cases/year) and ninth (2.8% of all
cancers i.e., 244,000 cases/year) most prevalent cancer worldwide in men and women, respectively. Although
multiple choices of therapies are offered for Hepatocellular Carcinoma (HCC) like liver resection
or transplant, radiofrequency ablation, transarterial chemoembolization, radioembolization, and systemic
targeted agent, by the time of diagnosis, most of the cases of HCC are in an advanced stage, which
renders therapies like liver transplant or resection and local ablation impractical; and targeted therapy
has its shortcomings like general toxicity, imprecise selectivity, several adversative reactions, and resistance
development. Therefore, novel drugs with specificity and selectivity are needed to provide the potential
therapeutic response. Various researches have shown the potential of phytomedicines in liver
cancer by modulating cell growth, invasion, metastasis, and apoptosis. However, their therapeutic potential
is held up by their unfavorable properties like stability, poor water solubility, low absorption, and
quick metabolism. Nonetheless, the advancement of nanotechnology-based innovative nanocarrier formulations
has improved the phytomedicines’ profile to be used in the treatment of liver cancer. Nanocarriers
not only improve the solubility and stability of phytomedicines but also extend their residence in
plasma and accomplish specificity. In this review, we summarize the advancements introduced by
nanotechnology in the treatment of liver cancer. In particular, we discuss quite a few applications of
nanophytomedicines like curcumin, quercetin, epigallocatechin-3-gallate, berberine, apigenin, triptolide,
and resveratrol in liver cancer treatment.
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Affiliation(s)
- Sachin Kumar
- Department of Pharmacology, Delhi Institute of Pharmaceutical Sciences and Research, Sector-III, MB Road, PushpVihar, New Delhi-110017, India
| | - Faizana Fayaz
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-III, MB Road, PushpVihar, New Delhi-110017, India
| | - Faheem Hyder Pottoo
- Department of Pharmacology, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, P.O. Box 1982, Dammam, 31441, Saudi Arabia
| | - Sakshi Bajaj
- Department of Herbal Drug Technology, Delhi Institute of Pharmaceutical Sciences and Research, Sector-III, MB Road, PushpVihar, New Delhi-110017, India
| | - Satish Manchanda
- Department of Pharmaceutics, Delhi Institute of Pharmaceutical Sciences and Research, Sector-III, MB Road, PushpVihar, New Delhi-110017, India
| | - Himangini Bansal
- Department of Pharmaceutical Chemistry, Delhi Institute of Pharmaceutical Sciences and Research, Sector-III, MB Road, PushpVihar, New Delhi-110017, India
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Friedlaender A, Drilon A, Banna GL, Peters S, Addeo A. The METeoric rise of MET in lung cancer. Cancer 2020; 126:4826-4837. [PMID: 32888330 DOI: 10.1002/cncr.33159] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2020] [Revised: 07/27/2020] [Accepted: 07/29/2020] [Indexed: 11/07/2022]
Abstract
Over the years, there has been a continuous increase in clinically relevant driver mutations in patients with non-small cell lung cancer (NSCLC). Among these, dysregulated activation of the MET tyrosine kinase receptor has gained importance due to the recent development of quite effective treatments. MET dysregulation encompasses a heterogeneous array of alterations leading to the prolonged activation of the cellular MET (c-MET or MET) receptor and downstream proliferation pathways. It can arise through several mechanisms, including gene amplification, overexpression of the receptor and/or its ligand hepatocyte growth factor, and the acquisition of activating mutations. MET mutations are found in approximately 3% to 5% of patients with NSCLC, mainly adenocarcinoma, and are overrepresented in the sarcomatoid subtype. De novo MET amplifications are found in 1% to 5% of NSCLC cases, also predominantly in adenocarcinoma. In the current review, the authors discussed the biology of MET, how to diagnose clinically relevant alterations, and the rising clinical importance of these alterations in light of the emergence of multiple targeted therapies, both within the context of MET as a driver of resistance and in its own right.
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Affiliation(s)
- Alex Friedlaender
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
| | - Alexander Drilon
- Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.,Weill Cornell Medical College, New York, New York
| | | | - Solange Peters
- Oncology Department, Vaudois University Medical Center, Lausanne University, Lausanne, Switzerland
| | - Alfredo Addeo
- Department of Oncology, University Hospital of Geneva, Geneva, Switzerland
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Kudo M, Morimoto M, Moriguchi M, Izumi N, Takayama T, Yoshiji H, Hino K, Oikawa T, Chiba T, Motomura K, Kato J, Yasuchika K, Ido A, Sato T, Nakashima D, Ueshima K, Ikeda M, Okusaka T, Tamura K, Furuse J. A randomized, double-blind, placebo-controlled, phase 3 study of tivantinib in Japanese patients with MET-high hepatocellular carcinoma. Cancer Sci 2020; 111:3759-3769. [PMID: 32716114 PMCID: PMC7541009 DOI: 10.1111/cas.14582] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 07/17/2020] [Accepted: 07/19/2020] [Indexed: 12/17/2022] Open
Abstract
A previous randomized phase 2 study of hepatocellular carcinoma revealed that the c‐Met inhibitor tivantinib as second‐line treatment significantly prolonged progression‐free survival in a subpopulation whose tumor samples highly expressed c‐Met (MET‐high). Accordingly, this phase 3 study was conducted to evaluate the efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. This randomized, double‐blind, placebo‐controlled study was conducted at 60 centers in Japan. Hepatocellular carcinoma patients with one prior sorafenib treatment and those with MET‐high tumor samples were eligible for inclusion. Registered patients were randomly assigned to either the tivantinib or placebo group at a 2:1 ratio and were treated with twice‐a‐day oral tivantinib (120 mg bid) or placebo until the discontinuation criteria were met. The primary endpoint was progression‐free survival while the secondary endpoints included overall survival and safety. Between January 2014 and June 2016, 386 patients provided consent, and 195 patients were randomized to the tivantinib (n = 134) or placebo (n = 61) group. Median progression‐free survival was 2.8 (95% confidence interval: 2.7‐2.9) and 2.3 (1.5‐2.8) mo in the tivantinib and placebo groups, respectively (hazard ratio = 0.74, 95% confidence interval: 0.52‐1.04, P = .082). Median overall survival was 10.3 (95% confidence interval: 8.1‐11.6) and 8.5 (6.2‐11.4) mo in the tivantinib and placebo group, respectively (hazard ratio = 0.82, 95% confidence interval: 0.58‐1.15). The most common tivantinib‐related grade ≥3 adverse events were neutropenia (31.6%), leukocytopenia (24.8%), and anemia (12.0%). This study did not confirm the significant efficacy of tivantinib as a second‐line treatment for Japanese patients with MET‐high hepatocellular carcinoma. (NCT02029157).
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Affiliation(s)
- Masatoshi Kudo
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Manabu Morimoto
- Department of Hepatobiliary and Pancreatic Medical Oncology, Kanagawa Cancer Center, Kanagawa, Japan
| | - Michihisa Moriguchi
- Department of Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kyoto, Japan
| | - Namiki Izumi
- Department of Gastroenterology and Hepatology, Musashino Red Cross Hospital, Tokyo, Japan
| | - Tetsuji Takayama
- Department of Gastroenterology and Oncology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan
| | - Hitoshi Yoshiji
- Department of Gastroenterology, Nara Medical University, Nara, Japan
| | - Keisuke Hino
- Department of Hepatology and Pancreatology, Kawasaki Medical School, Okayama, Japan
| | - Takayoshi Oikawa
- Department of Internal Medicine, Division of Hepatology, Iwate Medical University, Iwate, Japan
| | - Tetsuhiro Chiba
- Department of Gastroenterology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kenta Motomura
- Department of Hepatology, Aso Iizuka Hospital, Fukuoka, Japan
| | - Junko Kato
- Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan
| | - Kentaro Yasuchika
- Department of Surgery, Division of Hepatobiliary Pancreatic Surgery and Transplantation, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akio Ido
- Department of Gastroenterology, Kagoshima University Medical and Dental Hospital, Kagoshima, Japan
| | - Takashi Sato
- R&D Division, Kyowa Kirin Co., Ltd, Tokyo, Japan
| | | | - Kazuomi Ueshima
- Department of Gastroenterology and Hepatology, Faculty of Medicine, Kindai University, Osaka, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuo Tamura
- General Medical Research Center, Faculty of Medicine, Fukuoka University, Fukuoka, Japan
| | - Junji Furuse
- Department of Medical Oncology, Faculty of Medicine, Kyorin University, Tokyo, Japan
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Zangouei AS, Barjasteh AH, Rahimi HR, Mojarrad M, Moghbeli M. Role of tyrosine kinases in bladder cancer progression: an overview. Cell Commun Signal 2020; 18:127. [PMID: 32795296 PMCID: PMC7427778 DOI: 10.1186/s12964-020-00625-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/02/2020] [Indexed: 12/20/2022] Open
Abstract
Background Bladder cancer (BCa) is a frequent urothelial malignancy with a high ratio of morbidity and mortality. Various genetic and environmental factors are involved in BCa progression. Since, majority of BCa cases are diagnosed after macroscopic clinical symptoms, it is required to find efficient markers for the early detection. Receptor tyrosine-kinases (RTKs) and non-receptor tyrosine-kinases (nRTKs) have pivotal roles in various cellular processes such as growth, migration, differentiation, and metabolism through different signaling pathways. Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies. Main body For the first time in present review we have summarized all of the reported tyrosine-kinases which have been significantly associated with the clinicopathological features of BCa patients. Conclusions This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis.
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