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Yang Y, Zhang L, Munyurangabo G, Zhou Y, He S, Zhang P, Yu X, Kong G. Deficiency of the histone H3K36 methyltransferase SETD2 inhibits the proliferation and migration of hepatocellular carcinoma cells. J Cancer 2024; 15:6479-6489. [PMID: 39668826 PMCID: PMC11632984 DOI: 10.7150/jca.97844] [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: 04/28/2024] [Accepted: 10/12/2024] [Indexed: 12/14/2024] Open
Abstract
Background: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. SETD2, the only known methyltransferase catalyzes the trimethylation of histone H3 lysine 36 (H3K36), has been reported to be associated with several cancers. However, the function of SETD2 in HCC is unclear. This work aimed to investigate the function and mechanism of SETD2 in HCC through bioinformatics analysis and cell experiments. Methods: SETD2 expression and its relationship with prognosis were evaluated in The Cancer Genome Atlas (TCGA)-LIHC cohort, and the effects of SETD2 silencing and overexpression on HCC cell lines were assesed via CCK-8, colony formation and wound healing assays. RNA-seq analysis, western blotting and chromatin immunoprecipitation (ChIP) assays were used to assess the potential mechanism of action of SETD2 in HCC. Results: The results indicated that SETD2 expression is upregulated and that high SETD2 expression is related to a poor prognosis in HCC patients. SETD2 silencing inhibited proliferation and migration, and SETD2 overexpression promoted proliferation and migration in HCC cells. RNA-seq data revealed that the differentially expressed genes were enriched in the fibroblast growth factor receptor signaling pathway. FGFBP1, which was an FGF-binding protein and could enhance FGFR signaling pathway by releasing FGF from the extracellular matrix, was among the top 10 DEGs. Furthermore, the expression of FGFBP1 was decreased in SETD2-silenced BEL-7402 cells. The expression level of phosphorylated ERK, a downstream effector of FGFR, was positively correlated with the expression level of SETD2. In addition, ChIP-qPCR confirmed that the H3K36me3 modification occured on the gene body of FGFBP1. Conclusions: Our findings highlight the role of SETD2/H3K36me3 in promoting HCC proliferation and migration via the FGFR pathway. Our study advances our understanding of epigenetic dysregulation during HCC progression and provides a rationale for the application of SETD2 as a potential diagnostic biomarker and therapeutic target in HCC.
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Affiliation(s)
- Yi Yang
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Center for Tumor and Immunology, the Precision Medical Institute, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Linlin Zhang
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Center for Tumor and Immunology, the Precision Medical Institute, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Gustave Munyurangabo
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Ying Zhou
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
- Center for Tumor and Immunology, the Precision Medical Institute, Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Shuyang He
- Queen Mary school, Nanchang University, Nanchang, Jiangxi, People's Republic of China
| | - Peihua Zhang
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Xiao Yu
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
| | - Guangyao Kong
- Department of Oncology, National-Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, People's Republic of China
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Mahaamnad N, Pocasap P, Kukongviriyapan V, Senggunprai L, Prawan A, Kongpetch S. Dual blockage of PI3K-mTOR and FGFR induced autophagic cell death in cholangiocarcinoma cells. Heliyon 2024; 10:e31112. [PMID: 38799762 PMCID: PMC11126846 DOI: 10.1016/j.heliyon.2024.e31112] [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: 09/25/2023] [Revised: 05/09/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Purpose To assess the impact of concurrent inhibition of the FGFR and PI3K/mTOR signaling pathways on oncogenic characteristics in cholangiocarcinoma (CCA) cells, including proliferation, autophagy, and cell death. Materials and methods KKU-213A, KKU-100, and KKU-213C cells were treated with either infigratinib or PKI-402 alone or in combination. Cell viability and cell death were evaluated using the sulforhodamine B (SRB) assay and acridine orange/ethidium bromide (AO/EB) staining. Cell cycle progression and apoptotic cell death were analyzed by flow cytometry. Western blotting was performed to assess the expression of proteins involved in cell cycle regulation and autophagy. Additionally, AO staining was employed to assess autophagic induction. Results The combination of infigratinib and PKI-402 showed a remarked synergistic suppression in cell viability in both CCA cell lines compared to treatment with single inhibitors. This antiproliferative effect was associated with cell cycle arrest in the G2-M phase and a decrease in the expression of cyclin A and cyclin B1 in CCA cells. Furthermore, the combination treatment induced apoptotic cell death to a greater extent than treatment with a single inhibitor. Infigratinib enhanced the induction of autophagy by PKI-402, as evidenced by marked increases of autophagic vacuoles stained acridine orange, levels of LC3B-II and suppression of levels of p-mTOR and. Notably, inhibition of autophagic flux by chloroquine prevented cell death induced by the combination treatment. Conclusions This study demonstrated that concurrent inhibition of the key FGFR/PI3K/mTOR pathways in CCA carcinogenesis enhances the suppression of CCA cells. The present findings indicate potential clinical implications for using combination treatment modalities in CCA therapy.
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Affiliation(s)
- Narumon Mahaamnad
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Piman Pocasap
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
| | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Laddawan Senggunprai
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Auemduan Prawan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
| | - Sarinya Kongpetch
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand
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Shan KS, Dalal S, Thaw Dar NN, McLish O, Salzberg M, Pico BA. Molecular Targeting of the Fibroblast Growth Factor Receptor Pathway across Various Cancers. Int J Mol Sci 2024; 25:849. [PMID: 38255923 PMCID: PMC10815772 DOI: 10.3390/ijms25020849] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/19/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that are involved in the regulation of cell proliferation, survival, and development. FGFR alterations including amplifications, fusions, rearrangements, and mutations can result in the downstream activation of tyrosine kinases, leading to tumor development. Targeting these FGFR alterations has shown to be effective in treating cholangiocarcinoma, urothelial carcinoma, and myeloid/lymphoid neoplasms, and there are currently four FGFR inhibitors approved by the Food and Drug Administration (FDA). There have been developments in multiple agents targeting the FGFR pathway, including selective FGFR inhibitors, ligand traps, monoclonal antibodies, and antibody-drug conjugates. However, most of these agents have variable and low responses, with some intolerable toxicities and acquired resistances. This review will summarize previous clinical experiences and current developments in agents targeting the FGFR pathway, and will also discuss future directions for FGFR-targeting agents.
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Affiliation(s)
- Khine S. Shan
- Memorial Health Care, Division of Hematology and Oncology, Pembroke Pines, FL 33028, USA; (S.D.); (N.N.T.D.); (O.M.); (M.S.)
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Storandt MH, Jin Z, Mahipal A. Pemigatinib in cholangiocarcinoma with a FGFR2 rearrangement or fusion. Expert Rev Anticancer Ther 2022; 22:1265-1274. [PMID: 36408971 DOI: 10.1080/14737140.2022.2150168] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) accounts for approximately 3% of gastrointestinal malignancies and is associated with a high mortality rate. Recent progress in the understanding of cholangiocarcinoma tumorigenesis and molecular markers has led to the development of several targeted therapies applicable to this disease. Fibroblast growth factor receptor 2 (FGFR2) gene fusion or translocation, resulting in constitutive activation of the FGFR tyrosine kinase, has been identified as a driver of oncogenesis in 10-15% of intrahepatic CCA. Pemigatinib is an FGFR inhibitor that has demonstrated survival benefit in the second line setting for treatment of CCA with FGFR2 fusion or rearrangement refractory to chemotherapy. Pemigatinib was the first targeted therapy to be approved by the FDA for treatment of cholangiocarcinoma. AREAS COVERED This article reviews FGFR and its dysregulation in oncogenesis, FGFR inhibitors, especially pemigatinib, utilized in treatment of CCA, common adverse events associated with FGFR inhibitors, and future directions in the field of targeted drug development for CCA. EXPERT OPINION FGFR inhibitors, including pemigatinib, have shown promise in the management of CCA with FGFR2 fusion or rearrangement; however, acquired resistance remains a major barrier in the field of FGFR inhibitors and requires further study.
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Affiliation(s)
| | - Zhaohui Jin
- Department of Oncology, Mayo Clinic, Rochester, MN, USA
| | - Amit Mahipal
- Department of Oncology, Mayo Clinic, Rochester, MN, USA.,Department of Oncology, University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, OH, USA
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Chakrabarti S, Finnes HD, Mahipal A. Fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma: current status, insight on resistance mechanisms and toxicity management. Expert Opin Drug Metab Toxicol 2022; 18:85-98. [PMID: 35129006 DOI: 10.1080/17425255.2022.2039118] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 02/03/2022] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Cholangiocarcinoma (CCA) frequently presents with an advanced disease precluding curative surgery and shows modest response to chemotherapy. Advancements in genomic profiling have unfolded critical pathophysiologic underpinnings of CCA, leading to the development of targeted therapies with encouraging early results. Of the targetable genomic alterations, fibroblast growth factor receptor-2 (FGFR-2) fusions or rearrangements are present in 10-15% of patients with intrahepatic CCA. Clinical trials demonstrating significant antitumor activity of FGFR inhibitors in FGFR-2 fusion or rearrangement enriched chemotherapy-refractory patients led to FDA approval of FGFR inhibitors, pemigatinib and infigratinib, in the second-line setting. We identified peer-reviewed articles on FGFR inhibitors utilizing the PubMed database published between 2015 and 2021. AREAS COVERED This article provides an overview of clinical and biological characteristics of FGFR-driven CCA, pharmacology and antitumor activity of currently available FGFR inhibitors, and the evolving knowledge of drug resistance mechanisms. Additionally, toxicities associated with FGFR inhibitor use and their management have been described. EXPERT OPINION The development of FGFR inhibitors is a significant advancement in the therapeutic paradigm of advanced CCA. Ongoing research utilizing FGFR inhibitors in treatment-naïve patients, elucidation of resistance mechanisms to harness future trials, and exploration of combination strategies will transform the treatment landscape of CCA.
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Affiliation(s)
- Sakti Chakrabarti
- Department of Hematology-Oncology, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Heidi D Finnes
- Pharmacy Cancer Research, Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
| | - Amit Mahipal
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA
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Li K, Deng X, Feng G, Chen Y. Knockdown of Bcl-2-Associated Athanogene-3 Can Enhance the Efficacy of BGJ398 via Suppressing Migration and Inducing Apoptosis in Gastric Cancer. Dig Dis Sci 2021; 66:3036-3044. [PMID: 33089486 DOI: 10.1007/s10620-020-06640-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 09/24/2020] [Indexed: 12/13/2022]
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignancies of the digestive tract worldwide, and cancer cell resistance against anticancer drugs remains a major challenge for GC treatment. Nvp-BGJ398 (BGJ398) is considered as a common drug for cancer treatment; however, Bcl-2-associated athanogene-3 (BAG3) plays an important role in drug resistance. AIMS To investigate the function of BAG3 on the sensitivity of GC cells to BGJ398. METHODS The expression of BAG3 in GC cells and GC resistance cells was examined by qRT-PCR and western blot. The resistance to BGJ398 was detected by viability assay, and a half-maximal inhibitory concentration (IC50) was calculated. The cell migration and apoptosis were determined by wound-healing assay and flow cytometry assay. RESULTS BAG3 was highly expressed in drug-resistant cells Fu97R and Snu16R. BAG3 was also associated with sensitivity of Snu16 cells to BGJ398, promoting migration but inhibiting apoptosis. However, knockdown of heat shock transcription factor 1 (HSF1) suppressed BAG3 expression and lowered the sensitivity to BGJ398 in Snu16R cells. Knockdown of BAG3 inhibited tumor growth and cell apoptosis but induced cell apoptosis and amplified the sensitivity to BGJ398 in Snu16R cells, followed by enhancing BGJ398-induced antitumor function in a Snu16R-derived xenograft mouse model. CONCLUSION The mechanism of resistance to BGJ398 in GC is mediated by BAG3/HSF1, and combined treatment with shBAG3 could improve the efficacy of BGJ398 in GC. Thus, BAG3-targeted therapy improves the antitumor efficacy of BGJ398, which might provide a novel therapeutic strategy for GC.
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Affiliation(s)
- Ke Li
- Department of General Surgery, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Qizhi Road, Jiangbei District, Chongqing, 400000, China
| | - Xiang Deng
- Department of General Surgery, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Qizhi Road, Jiangbei District, Chongqing, 400000, China
| | - Guangjing Feng
- Department of General Surgery, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Qizhi Road, Jiangbei District, Chongqing, 400000, China.
| | - Yi Chen
- Department of General Surgery, Chongqing Traditional Chinese Medicine Hospital, No. 6 Panxi Qizhi Road, Jiangbei District, Chongqing, 400000, China
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Lang SA, Bednarsch J, Czigany Z, Joechle K, Kroh A, Amygdalos I, Strnad P, Bruns T, Heise D, Ulmer F, Neumann UP. Liver transplantation in malignant disease. World J Clin Oncol 2021; 12:623-645. [PMID: 34513597 PMCID: PMC8394155 DOI: 10.5306/wjco.v12.i8.623] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 06/15/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver transplantation for malignant disease has gained increasing attention as part of transplant oncology. Following the implementation of the Milan criteria, hepatocellular carcinoma (HCC) was the first generally accepted indication for transplantation in patients with cancer. Subsequently, more liberal criteria for HCC have been developed, and research on this topic is still ongoing. The evident success of liver transplantation for HCC has led to the attempt to extend its indication to other malignancies. Regarding perihilar cholangiocarcinoma, more and more evidence supports the use of liver transplantation, especially after neoadjuvant therapy. In addition, some data also show a benefit for selected patients with very early stage intrahepatic cholangiocarcinoma. Hepatic epithelioid hemangioendothelioma is a very rare but nonetheless established indication for liver transplantation in primary liver cancer. In contrast, patients with hepatic angiosarcoma are currently not considered to be optimal candidates. In secondary liver tumors, neuroendocrine cancer liver metastases are an accepted but comparability rare indication for liver transplantation. Recently, some evidence has been published supporting the use of liver transplantation even for colorectal liver metastases. This review summarizes the current evidence for liver transplantation for primary and secondary liver cancer.
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Affiliation(s)
- Sven Arke Lang
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Jan Bednarsch
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Zoltan Czigany
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Katharina Joechle
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Andreas Kroh
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Iakovos Amygdalos
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Pavel Strnad
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Tony Bruns
- Department of Internal Medicine III, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Daniel Heise
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Florian Ulmer
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
| | - Ulf Peter Neumann
- Department of Surgery and Transplantation, University Hospital RWTH Aachen, Aachen 52074, Germany
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Terp MG, Jacobsen K, Molina MA, Karachaliou N, Beck HC, Bertran-Alamillo J, Giménez-Capitán A, Cardona AF, Rosell R, Ditzel HJ. Combined FGFR and Akt pathway inhibition abrogates growth of FGFR1 overexpressing EGFR-TKI-resistant NSCLC cells. NPJ Precis Oncol 2021; 5:65. [PMID: 34267282 PMCID: PMC8282882 DOI: 10.1038/s41698-021-00208-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2021] [Accepted: 06/22/2021] [Indexed: 01/11/2023] Open
Abstract
EGFR tyrosine kinase inhibitor (TKI) resistance in non-small cell lung cancer (NSCLC) patients is inevitable. Identification of resistance mechanisms and corresponding targeting strategies can lead to more successful later-line treatment in many patients. Using spectrometry-based proteomics, we identified increased fibroblast growth factor receptor 1 (FGFR1) expression and Akt activation across erlotinib, gefitinib, and osimertinib EGFR-TKI-resistant cell line models. We show that while combined EGFR-TKI and FGFR inhibition showed some efficacy, simultaneous inhibition of FGFR and Akt or PI3K induced superior synergistic growth inhibition of FGFR1-overexpressing EGFR-TKI-resistant NSCLC cells. This effect was confirmed in vivo. Only dual FGFR and Akt inhibition completely blocked the resistance-mediating signaling pathways downstream of Akt. Further, increased FGFR1 expression was associated with significantly lower PFS in EGFR-TKI-treated NSCLC patients, and increased FGFR1 were demonstrated in a few post- vs. pre-EGFR-TKI treatment clinical biopsies. The superior therapeutic benefit of combining FGFR and Akt inhibitors provide the rationale for clinical trials of this strategy.
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Affiliation(s)
- Mikkel G Terp
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Kirstine Jacobsen
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark
| | - Miguel Angel Molina
- Laboratory of Oncology, Pangaea Biotech, Quiron Dexeus University Hospital, Barcelona, Spain
| | - Niki Karachaliou
- Instituto Oncológico Dr. Rosell, University Hospital Sagrat Cor, Barcelona, Spain.,Global Clinical Development, Merck Healthcare KGaA, Darmstadt, Germany
| | - Hans C Beck
- Center for Clinical Proteomics, Odense University Hospital, Odense C, Denmark
| | - Jordi Bertran-Alamillo
- Laboratory of Oncology, Pangaea Biotech, Quiron Dexeus University Hospital, Barcelona, Spain
| | - Ana Giménez-Capitán
- Laboratory of Oncology, Pangaea Biotech, Quiron Dexeus University Hospital, Barcelona, Spain
| | - Andrés F Cardona
- Thoracic Oncology Unit, Clinical and Translational Oncology Group, Clinica del Country, Bogotá, Colombia
| | - Rafael Rosell
- Laboratory of Oncology, Pangaea Biotech, Quiron Dexeus University Hospital, Barcelona, Spain.,Instituto Oncológico Dr. Rosell, Quiron-Dexeus University Hospital, Barcelona, Spain.,Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain.,Germans Trias i Pujol, Health Sciences Institute and Hospital, Badalona, Spain
| | - Henrik J Ditzel
- Department of Cancer and Inflammation Research, Institute of Molecular Medicine, University of Southern Denmark, Odense C, Denmark. .,Department of Oncology, Odense University Hospital, Odense C, Denmark. .,Academy of Geriatric Cancer Research (AgeCare), Odense University Hospital, Odense C, Denmark.
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FGFR Inhibitors in Oncology: Insight on the Management of Toxicities in Clinical Practice. Cancers (Basel) 2021; 13:cancers13122968. [PMID: 34199304 PMCID: PMC8231807 DOI: 10.3390/cancers13122968] [Citation(s) in RCA: 98] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 06/07/2021] [Accepted: 06/08/2021] [Indexed: 12/31/2022] Open
Abstract
Simple Summary FGFR inhibitors evolved as therapeutic options in cholangiocarcinoma and urothelial malignancies. Given the implications of FGFR pathway in various physiological functions, FGFR inhibitors are known to cause unique toxicities. In this review, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. Abstract Fibroblast Growth Factor receptor (FGFR) pathway aberrations have been implicated in approximately 7% of the malignancies. As our knowledge of FGFR aberrations in cancer continues to evolve, FGFR inhibitors emerged as potential targeted therapeutic agents. The promising results of pemigatinib and infigratinib in advanced unresectable cholangiocarcinoma harboring FGFR2 fusions or rearrangement, and erdafitinib in metastatic urothelial carcinoma with FGFR2 and FGFR3 genetic aberrations, lead to their accelerated approval by the United States (USA) FDA. Along with these agents, many phase II/III clinical trials are currently evaluating the use of derazantinib, infigratinib, and futibatinib either alone or in combination with immunotherapy. Despite the encouraging results seen with FGFR inhibitors, resistance mechanisms and side effect profile may limit their clinical utility. A better understanding of the unique FGFR-inhibitor-related toxicities would invariably help us in the prevention and effective management of FGFR-inhibitor-induced adverse events thereby enhancing their clinical benefit. Herein, we summarized the physiology of FGF/FGFR signaling and briefly discussed the possible mechanisms that could lead to FGFR inhibitor resistance and side effects. In addition, we proposed treatment guidelines for the management of FGFR-inhibitor-associated toxicities. This work would invariably help practicing oncologists to effectively manage the unique toxicities of FGFR inhibitors.
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Vitale G, Cozzolino A, Malandrino P, Minotta R, Puliani G, Saronni D, Faggiano A, Colao A. Role of FGF System in Neuroendocrine Neoplasms: Potential Therapeutic Applications. Front Endocrinol (Lausanne) 2021; 12:665631. [PMID: 33935975 PMCID: PMC8080021 DOI: 10.3389/fendo.2021.665631] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Accepted: 03/22/2021] [Indexed: 12/16/2022] Open
Abstract
Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from neuroendocrine cells dispersed in different organs. Receptor tyrosine kinases are a subclass of tyrosine kinases with a relevant role in several cellular processes including proliferation, differentiation, motility and metabolism. Dysregulation of these receptors is involved in neoplastic development and progression for several tumors, including NENs. In this review, we provide an overview concerning the role of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) system in the development and progression of NENs, the occurrence of fibrotic complications and the onset of drug-resistance. Although no specific FGFR kinase inhibitors have been evaluated in NENs, several clinical trials on multitarget tyrosine kinase inhibitors, acting also on FGF system, showed promising anti-tumor activity with an acceptable and manageable safety profile in patients with advanced NENs. Future studies will need to confirm these issues, particularly with the development of new tyrosine kinase inhibitors highly selective for FGFR.
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Affiliation(s)
- Giovanni Vitale
- Laboratory of Geriatric and Oncologic Neuroendocrinology Research, Istituto Auxologico Italiano, IRCCS, Cusano Milanino, Italy
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Alessia Cozzolino
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Pasqualino Malandrino
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, Catania, Italy
| | - Roberto Minotta
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
| | - Giulia Puliani
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
- Oncological Endocrinology Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Davide Saronni
- Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy
| | - Antongiulio Faggiano
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy
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Legeai-Mallet L, Savarirayan R. Novel therapeutic approaches for the treatment of achondroplasia. Bone 2020; 141:115579. [PMID: 32795681 DOI: 10.1016/j.bone.2020.115579] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 08/06/2020] [Indexed: 02/08/2023]
Abstract
Achondroplasia is the most common form of human dwarfism. The molecular basis of achondroplasia was elucidated in 1994 with the identification of the fibroblast growth factor receptor 3 (FGFR3) as the causative gene. Missense mutations causing achondroplasia result in activation of FGFR3 and its downstream signaling pathways, disturbing chondrogenesis, osteogenesis, and long bone elongation. A more accurate understanding of the clinical and molecular aspects of achondroplasia has allowed new therapeutic approaches to be developed. These are based on: clear understanding of the natural history of the disease; proof-of-concept preclinical studies in mouse models; and the current state of knowledge regarding FGFR3 and related growth plate homeostatic pathways. This review provides a brief overview of the preclinical mouse models of achondroplasia that have led to new, non-surgical therapeutic strategies being assessed and applied to children with achondroplasia through pioneering clinical trials.
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Affiliation(s)
- Laurence Legeai-Mallet
- Université de Paris, Imagine Institute, Laboratory of Molecular and Physiopathological Bases of Osteochondrodysplasia, INSERM UMR 1163, F-75015 Paris, France.
| | - Ravi Savarirayan
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, University of Melbourne, Parkville, Victoria 3052, Australia.
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12
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Maki MAA, Cheah SC, Bayazeid O, Kumar PV. Cyclodextrin inclusion complex inhibits circulating galectin-3 and FGF-7 and affects the reproductive integrity and mobility of Caco-2 cells. Sci Rep 2020; 10:17468. [PMID: 33060727 PMCID: PMC7562932 DOI: 10.1038/s41598-020-74467-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Accepted: 09/30/2020] [Indexed: 02/08/2023] Open
Abstract
Galectin-3 (Gal-3) is a carbohydrate-binding protein, that promotes angiogenesis through mediating angiogenic growth factors such as vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). There is strong evidence confirming FGF involvement in tumor growth and progression by disrupting cell proliferation and angiogenesis. In this study, we investigated the effect of β-cyclodextrin:everolimus:FGF-7 inclusion complex (Complex) on Caco-2 cell migration, cell motility and colony formation. In addition, we examined the inhibitory effect of the Complex on the circulating proteins; Gal-3 and FGF-7. Swiss Target Prediction concluded that Gal-3 and FGF are possible targets for β-CD. Results of the chemotaxis cell migration assay on Caco-2 cell line revealed that the Complex has higher reduction in cell migration (78.3%) compared to everolimus (EV) alone (58.4%) which is possibly due to the synergistic effect of these molecules when used as a combined treatment. Moreover, the Complex significantly decreased the cell motility in cell scratch assay, less than 10% recovery compared to the control which has ~ 45% recovery. The Complex inhibited colony formation by ~ 75% compared to the control. Moreover, the Complex has the ability to inhibit Gal-3 with minimum inhibitory concentration of 33.46 and 41 for β-CD and EV, respectively. Additionally, β-CD and β-CD:EV were able to bind to FGF-7 and decreased the level of FGF-7 more than 80% in cell supernatant. This confirms Swiss Target Prediction result that predicted β-CD could target FGF. These findings advance the understanding of the biological effects of the Complex which reduced cell migration, cell motility and colony formation and it is possibly due to inhibiting circulating proteins such as; Gal-3 and FGF-7.
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Affiliation(s)
| | - Shiau-Chuen Cheah
- Faculty of Medicine and Health Sciences, UCSI University, Taman Connaught, Cheras, 56000, Kuala Lumpur, Malaysia
| | - Omer Bayazeid
- Faculty of Pharmacy, Department of Pharmacognosy, Hacettepe University, 06100, Ankara, Turkey
| | - Palanirajan Vijayaraj Kumar
- Faculty of Pharmaceutical Sciences, UCSI University, Taman Connaught, Cheras, 56000, Kuala Lumpur, Malaysia.
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13
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Luo H, Zhang T, Cheng P, Li D, Ogorodniitchouk O, Lahmamssi C, Wang G, Lan M. Therapeutic implications of fibroblast growth factor receptor inhibitors in a combination regimen for solid tumors. Oncol Lett 2020; 20:2525-2536. [PMID: 32782571 DOI: 10.3892/ol.2020.11858] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
A number of novel drugs targeting the fibroblast growth factor receptor (FGFR) signaling pathway have been developed, including mostly tyrosine kinase inhibitors, selective inhibitors or monoclonal antibodies. Multiple preclinical and clinical studies have been conducted worldwide to ascertain their effects on diverse solid tumors. Drugs, such as lenvatinib, dovitinib and other non-specific FGFR inhibitors, widely used in clinical practice, have been approved by the Food and Drug Administration for cancer therapy, although the majority of drugs remain in preclinical tests or clinical research. The resistance to a single agent for FGFR inhibition with synthetic lethal action may be overcome by a combination of therapeutic approaches and FGFR inhibitors, which could also enhance the sensitivity to other therapeutics. Therefore, the aim of the present review is to describe the pharmacological characteristics of FGFR inhibitors that may be combined with other therapeutic agents and the preclinical data supporting their combination. Additionally, their clinical implications and the remaining challenges for FGFR inhibitor combination regimens are discussed.
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Affiliation(s)
- Hong Luo
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Tao Zhang
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Peng Cheng
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Dong Li
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | | | - Chaimaa Lahmamssi
- Institut de Cancérologie Lucien Neuwirth, 42270 Saint Priest en Jarez, France
| | - Ge Wang
- Cancer Center, Institute of Surgical Research, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, P.R. China
| | - Meiling Lan
- Cancer Center, The Third Affiliated Hospital of Chongqing Medical University (Jie Er Hospital), Chongqing 401120, P.R. China
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14
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Identification of low-dose multidrug combinations for sunitinib-naive and pre-treated renal cell carcinoma. Br J Cancer 2020; 123:556-567. [PMID: 32439932 PMCID: PMC7435198 DOI: 10.1038/s41416-020-0890-y] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2019] [Revised: 04/04/2020] [Accepted: 04/23/2020] [Indexed: 12/11/2022] Open
Abstract
Background Combinations of drugs can improve the efficacy of cancer treatment, enable the reduction of side effects and the occurrence of acquired drug resistance. Methods We approached this challenge mathematically by using the validated technology called the Therapeutically Guided Multidrug Optimization (TGMO) method. In a set of genetically distinct human renal cell carcinoma (RCC) cell lines, either treated chronically with sunitinib (−ST) or sunitinib-naive, we identified cell line-specific low-dose-optimised drug combinations (ODC). Results Six cell-type-specific low-dose drug combinations for three sunitinib-naive as well as three sunitinib pre-treated cells were established. These ODCs effectively inhibited the RCC cell metabolic activity while being ineffective in non-cancerous cells. Based on a single screening test and three searches, starting with ten drugs, we identified highly efficacious drug mixtures containing four drugs. All ODCs contained AZD4547 (FGFR signalling pathway inhibitor) and pictilisib (pan-phosphatidylinositol 3-kinase inhibitor), but varied in the third and fourth drug. ODC treatment significantly decreased cell metabolic activity (up to 70%) and induced apoptosis, independent of the pretreatment with sunitinib. The ODCs outperformed sunitinib, the standard care for RCC. Moreover, short-term starvation potentiated the ODC activity. The translation of the 2D-based results to 3D heterotypic co-culture models revealed significant inhibition of the spheroid growth (up to 95%). Conclusion We demonstrate a promising low-dose drug combination development to obtain drug combinations effective in naive as well as resistant tumours. Nevertheless, we emphasise the need for further mechanistic investigation and preclinical development.
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15
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Krook MA, Lenyo A, Wilberding M, Barker H, Dantuono M, Bailey KM, Chen HZ, Reeser JW, Wing MR, Miya J, Samorodnitsky E, Smith AM, Dao T, Martin DM, Ciombor KK, Hays J, Freud AG, Roychowdhury S. Efficacy of FGFR Inhibitors and Combination Therapies for Acquired Resistance in FGFR2-Fusion Cholangiocarcinoma. Mol Cancer Ther 2020; 19:847-857. [PMID: 31911531 PMCID: PMC7359896 DOI: 10.1158/1535-7163.mct-19-0631] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2019] [Revised: 10/15/2019] [Accepted: 12/19/2019] [Indexed: 12/19/2022]
Abstract
The fibroblast growth factor receptor (FGFR) signaling pathway is aberrantly activated in approximately 15% to 20% of patients with intrahepatic cholangiocarcinoma. Currently, several FGFR kinase inhibitors are being assessed in clinical trials for patients with FGFR-altered cholangiocarcinoma. Despite evidence of initial responses and disease control, virtually all patients eventually develop acquired resistance. Thus, there is a critical need for the development of innovative therapeutic strategies to overcome acquired drug resistance. Here, we present findings from a patient with FGFR2-altered metastatic cholangiocarcinoma who enrolled in a phase II clinical trial of the FGFR inhibitor, infigratinib (BGJ398). Treatment was initially effective as demonstrated by imaging and tumor marker response; however, after 8 months on trial, the patient exhibited tumor regrowth and disease progression. Targeted sequencing of tumor DNA after disease progression revealed the FGFR2 kinase domain p.E565A and p.L617M single-nucleotide variants (SNV) hypothesized to drive acquired resistance to infigratinib. The sensitivities of these FGFR2 SNVs, which were detected post-infigratinib therapy, were extended to include clinically relevant FGFR inhibitors, including AZD4547, erdafitinib (JNJ-42756493), dovitinib, ponatinib, and TAS120, and were evaluated in vitro Through a proteomics approach, we identified upregulation of the PI3K/AKT/mTOR signaling pathway in cells harboring the FGFR2 p.E565A mutation and demonstrated that combination therapy strategies with FGFR and mTOR inhibitors may be used to overcome resistance to FGFR inhibition, specific to infigratinib. Collectively, these studies support the development of novel combination therapeutic strategies in addition to the next generation of FGFR inhibitors to overcome acquired resistance in patients.
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MESH Headings
- Antineoplastic Combined Chemotherapy Protocols/pharmacology
- Apoptosis
- Bile Duct Neoplasms/drug therapy
- Bile Duct Neoplasms/genetics
- Bile Duct Neoplasms/metabolism
- Bile Duct Neoplasms/pathology
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Cell Proliferation
- Cholangiocarcinoma/drug therapy
- Cholangiocarcinoma/genetics
- Cholangiocarcinoma/metabolism
- Cholangiocarcinoma/pathology
- Drug Resistance, Neoplasm
- Female
- Gene Expression Regulation, Neoplastic
- Humans
- Middle Aged
- Mutation
- Oncogene Proteins, Fusion/genetics
- Phenylurea Compounds/therapeutic use
- Prognosis
- Protein Kinase Inhibitors/therapeutic use
- Pyrimidines/therapeutic use
- Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 2/genetics
- Signal Transduction
- Tumor Cells, Cultured
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Affiliation(s)
- Melanie A Krook
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Alexandria Lenyo
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Max Wilberding
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Hannah Barker
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Mikayla Dantuono
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Kelly M Bailey
- Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
| | - Hui-Zi Chen
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Internal Medicine, Hematology and Oncology Fellowship Program, The Ohio State University, Columbus, Ohio
| | - Julie W Reeser
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Michele R Wing
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Jharna Miya
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | | | - Amy M Smith
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Thuy Dao
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Dorrelyn M Martin
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Kristen K Ciombor
- Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - John Hays
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
| | - Aharon G Freud
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
- Department of Pathology, The Ohio State University, Columbus, Ohio
| | - Sameek Roychowdhury
- Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio.
- Division of Medical Oncology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio
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16
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Kroh A, Walter J, Schüler H, Nolting J, Eickhoff R, Heise D, Neumann UP, Cramer T, Ulmer TF, Fragoulis A. A Newly Established Murine Cell Line as a Model for Hepatocellular Cancer in Non-Alcoholic Steatohepatitis. Int J Mol Sci 2019; 20:ijms20225658. [PMID: 31726709 PMCID: PMC6888677 DOI: 10.3390/ijms20225658] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2019] [Revised: 11/07/2019] [Accepted: 11/08/2019] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic steatohepatitis (NASH) has become a major risk factor for hepatocellular cancer (HCC) due to the worldwide increasing prevalence of obesity. However, the pathophysiology of NASH and its progression to HCC is incompletely understood. Thus, the aim of this study was to generate a model specific NASH-derived HCC cell line. A murine NASH-HCC model was conducted and the obtained cancer cells (N-HCC25) were investigated towards chromosomal aberrations, the expression of cell type-specific markers, dependency on nutrients, and functional importance of mTOR. N-HCC25 exhibited several chromosomal aberrations as compared to healthy hepatocytes. Hepatocytic (HNF4), EMT (Twist, Snail), and cancer stem cell markers (CD44, EpCAM, CK19, Sox9) were simultaneously expressed in these cells. Proliferation highly depended on the supply of glucose and FBS, but not glutamine. Treatment with a second generation mTOR inhibitor (KU-0063794) resulted in a strong decrease of cell growth in a dose-dependent manner. In contrast, a first generation mTOR inhibitor (Everolimus) only slightly reduced cell proliferation. Cell cycle analyses revealed that the observed growth reduction was most likely due to G1/G0 cell cycle arrest. These results indicate that N-HCC25 is a highly proliferative HCC cell line from a NASH background, which might serve as a suitable in vitro model for future investigations of NASH-derived HCC.
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Affiliation(s)
- Andreas Kroh
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Correspondence: ; Tel.: +49-241-80-89-501
| | - Jeanette Walter
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Herdit Schüler
- Institute of Human Genetics, Uniklinik RWTH Aachen, 52074 Aachen, Germany;
| | - Jochen Nolting
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Roman Eickhoff
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Daniel Heise
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
| | - Ulf Peter Neumann
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
- ESCAM—European Surgery Center Aachen Maastricht, 52074 Aachen, Germany
- ESCAM—European Surgery Center Aachen Maastricht, 6200 MD Maastricht, The Netherlands
| | - Thorsten Cramer
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
- ESCAM—European Surgery Center Aachen Maastricht, 52074 Aachen, Germany
- ESCAM—European Surgery Center Aachen Maastricht, 6200 MD Maastricht, The Netherlands
| | - Tom Florian Ulmer
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Surgery, Maastricht University Medical Center, 6200 MD Maastricht, The Netherlands
| | - Athanassios Fragoulis
- Department of General, Visceral and Transplantation Surgery, Uniklinik RWTH Aachen, 52074 Aachen, Germany; (J.W.); (J.N.); (R.E.); (D.H.); (U.P.N.); (T.C.); (T.F.U.); (A.F.)
- Department of Anatomy and Cell Biology, Uniklinik RWTH Aachen, 52074 Aachen, Germany
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17
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Maki MA, Kumar PV, Cheah SC, Siew Wei Y, Al-Nema M, Bayazeid O, Majeed ABBA. Molecular Modeling- Based Delivery System Enhances Everolimus-Induced Apoptosis in Caco-2 Cells. ACS OMEGA 2019; 4:8767-8777. [PMID: 31459966 PMCID: PMC6649008 DOI: 10.1021/acsomega.9b00109] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Accepted: 04/22/2019] [Indexed: 02/08/2023]
Abstract
Several studies have shown that the mammalian target of rapamycin (mTOR) inhibitor; everolimus (EV) improves patient survival in several types of cancer. However, the meaningful efficacy of EV as a single agent for the treatment of colorectal cancer (CRC) has failed to be proven in multiple clinical trials. Combination therapy is one of the options that could increase the efficacy and decrease the toxicity of the anticancer therapy. This study revealed that the β-cyclodextrin (β-CD):FGF7 complex has the potential to improve the antiproliferative effect of EV by preventing FGF receptor activation and by enhancing EV cellular uptake and intracellular retention. Molecular docking techniques were used to investigate the possible interaction between EV, β-CD, and FGF7. Molecular docking insights revealed that β-CD and EV are capable to form a stable inclusion complex with FGF at the molecular level. The aqueous solubility of the inclusion complex was increased (3.1 ± 0.23 μM) when compared to the aqueous solubility of pure EV (1.7 ± 0.16 μM). In addition, the in vitro cytotoxic activity of a FGF7:β-CD:EV complex on Caco-2 cell line was investigated using real-time xCELLigence technology. The FGF7:β-CD:EV complex has induced apoptosis of Caco-2 cells and shown higher cytotoxic activity than the parent drug EV. With the multitargets effect of β-CD:FGF7 and EV, the antiproliferative effect of EV was remarkably improved as the IC50 value of EV was reduced from 9.65 ± 1.42 to 1.87 ± 0.33 μM when compared to FGF7:β-CD:EV complex activity. In conclusion, the findings advance the understanding of the biological combinational effects of the β-CD:FGF7 complex and EV as an effective treatment to combat CRC.
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Affiliation(s)
- Marwan
Abdelmahmoud Abdelkarim Maki
- Faculty
of Pharmaceutical Sciences and Faculty of Medicine & Health
Sciences, UCSI University, no. 1, Jalan Menara Gading, Taman Connaught, Cheras 56000 Kuala Lumpur, Malaysia
| | - Palanirajan Vijayaraj Kumar
- Faculty
of Pharmaceutical Sciences and Faculty of Medicine & Health
Sciences, UCSI University, no. 1, Jalan Menara Gading, Taman Connaught, Cheras 56000 Kuala Lumpur, Malaysia
| | - Shiau-Chuen Cheah
- Faculty
of Pharmaceutical Sciences and Faculty of Medicine & Health
Sciences, UCSI University, no. 1, Jalan Menara Gading, Taman Connaught, Cheras 56000 Kuala Lumpur, Malaysia
| | - Yeong Siew Wei
- Faculty
of Pharmaceutical Sciences and Faculty of Medicine & Health
Sciences, UCSI University, no. 1, Jalan Menara Gading, Taman Connaught, Cheras 56000 Kuala Lumpur, Malaysia
| | - Mayasah Al-Nema
- Faculty
of Pharmaceutical Sciences and Faculty of Medicine & Health
Sciences, UCSI University, no. 1, Jalan Menara Gading, Taman Connaught, Cheras 56000 Kuala Lumpur, Malaysia
| | - Omer Bayazeid
- Faculty
of Pharmacy, Department of Pharmacognosy, Hacettepe University, 06100 Ankara, Turkey
| | - Abu Bakar Bin Abdul Majeed
- Faculty
of Pharmacy, Research Management Institute, Universiti Teknologi MARA, 42300 Shah Alam, Malaysia
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18
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Cai W, Song B, Ai H. Combined inhibition of FGFR and mTOR pathways is effective in suppressing ovarian cancer. Am J Transl Res 2019; 11:1616-1625. [PMID: 30972187 PMCID: PMC6456542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2018] [Accepted: 01/23/2019] [Indexed: 06/09/2023]
Abstract
The PI3K/AKT/mTOR signaling pathway is considered as a promising therapeutic target in the treatment of ovarian cancer (OC); however, inhibition of this pathway only exhibited moderate clinical efficacy when tested clinically. Combination of mTOR inhibitors with other anticancer compounds could improve the anticancer efficiency. Therefore, the concurrent inhibition of Fibroblast Growth Factor Receptor (FGFR) signaling pathway was evaluated in the present study. OC cell lines were treated with FGFR inhibitor BGJ398, mTOR inhibitor Rapamycin, or combined inhibition of both BGJ398 and Rapamycin. The results revealed that the growth and motility, expression of angiogenic markers and phosphorylation of associated proteins were affected in treated OC cells. Additionally, the anticancer effects of aforementioned inhibitors were evaluated using a murine tumor xenograft model. Combined treatment with BGJ398 and Rapamycin exhibited stronger inhibitory effects on the growth and motility of OC cells compared with BGJ398 or Rapamycin alone group. Furthermore, combined inhibition of FGFR and mTOR pathways by BGJ398 and Rapamycin induced remarkable cell cycle arrest and apoptosis in OC cells. Reduced tumor size in the xenograft was also observed following combined treatment but not in BGJ398 or Rapamycin alone group. The results in the present study revealed that combined inhibition of FGFR and mTOR pathways could be a promising therapeutic strategy in the treatment of patients with OC.
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Affiliation(s)
- Wang Cai
- The Department of Obstetrics and Gynecology, The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001, P. R. China
| | - Bing Song
- The First Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001, P. R. China
| | - Hao Ai
- The Third Affiliated Hospital of Jinzhou Medical UniversityJinzhou 121001, P. R. China
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19
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Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) are expressed throughout all stages of skeletal development. In the limb bud and in cranial mesenchyme, FGF signaling is important for formation of mesenchymal condensations that give rise to bone. Once skeletal elements are initiated and patterned, FGFs regulate both endochondral and intramembranous ossification programs. In this chapter, we review functions of the FGF signaling pathway during these critical stages of skeletogenesis, and explore skeletal malformations in humans that are caused by mutations in FGF signaling molecules.
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Affiliation(s)
- David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, United States.
| | - Pierre J Marie
- UMR-1132 Inserm (Institut national de la Santé et de la Recherche Médicale) and University Paris Diderot, Sorbonne Paris Cité, Hôpital Lariboisière, Paris, France
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20
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Schmidt KM, Dietrich P, Hackl C, Guenzle J, Bronsert P, Wagner C, Fichtner-Feigl S, Schlitt HJ, Geissler EK, Hellerbrand C, Lang SA. Inhibition of mTORC2/RICTOR Impairs Melanoma Hepatic Metastasis. Neoplasia 2018; 20:1198-1208. [PMID: 30404068 PMCID: PMC6224335 DOI: 10.1016/j.neo.2018.10.001] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Revised: 10/09/2018] [Accepted: 10/11/2018] [Indexed: 02/07/2023] Open
Abstract
Mammalian target of rapamycin complex 2 (mTORC2) with its pivotal component rapamycin-insensitive companion of mTOR (RICTOR) is the major regulator of AKT phosphorylation and is increasingly implicated in tumor growth and progression. In cutaneous melanoma, an extremely aggressive and highly metastatic disease, RICTOR overexpression is involved in tumor development and invasiveness. Therefore, we investigated the impact of RICTOR inhibition in melanoma cells in vitro and in vivo with special emphasis on hepatic metastasis. Moreover, our study focused on the interaction of tumor cells and hepatic stellate cells (HSC) which play a crucial role in the hepatic microenvironment. In silico analysis revealed increased RICTOR expression in melanoma cells and tissues and indicated higher expression in advanced melanoma stages and metastases. In vitro, transient RICTOR knock-down via siRNA caused a significant reduction of tumor cell motility. Using a syngeneic murine splenic injection model, a significant decrease in liver metastasis burden was detected in vivo. Moreover, stimulation of melanoma cells with conditioned medium (CM) from activated HSC or hepatocyte growth factor (HGF) led to a significant induction of AKT phosphorylation and tumor cell motility. Blocking of RICTOR expression in cancer cells diminished constitutive and HGF-induced AKT phosphorylation as well as cell motility. Interestingly, RICTOR blockade also led to an abrogation of CM-induced effects on AKT phosphorylation and motility in melanoma cells. In conclusion, these results provide first evidence for a critical role of mTORC2/RICTOR in melanoma liver metastasis via cancer cell/HSC interactions.
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Affiliation(s)
- Katharina M Schmidt
- Department of Surgery, Regensburg University Hospital, Franz-Josef-Strauss Allee 9, Regensburg, Germany.
| | - Peter Dietrich
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstrasse 17, Germany; Department of Medicine 1, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen, Germany.
| | - Christina Hackl
- Department of Surgery, Regensburg University Hospital, Franz-Josef-Strauss Allee 9, Regensburg, Germany.
| | - Jessica Guenzle
- Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, Germany.
| | - Peter Bronsert
- Institute for Surgical Pathology, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Strasse 115a, Germany; Tumorbank Comprehensive Cancer Center Freiburg, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Breisacher Strasse 115a, Germany.
| | - Christine Wagner
- Department of Surgery, Regensburg University Hospital, Franz-Josef-Strauss Allee 9, Regensburg, Germany.
| | - Stefan Fichtner-Feigl
- Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, Germany.
| | - Hans J Schlitt
- Department of Surgery, Regensburg University Hospital, Franz-Josef-Strauss Allee 9, Regensburg, Germany.
| | - Edward K Geissler
- Department of Surgery, Regensburg University Hospital, Franz-Josef-Strauss Allee 9, Regensburg, Germany.
| | - Claus Hellerbrand
- Institute of Biochemistry, Friedrich-Alexander University Erlangen-Nürnberg, Fahrstrasse 17, Germany.
| | - Sven A Lang
- Department of Surgery, Regensburg University Hospital, Franz-Josef-Strauss Allee 9, Regensburg, Germany; Department of General and Visceral Surgery, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Strasse 55, Germany.
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21
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Inhibition of mTORC2 component RICTOR impairs tumor growth in pancreatic cancer models. Oncotarget 2018; 8:24491-24505. [PMID: 28445935 PMCID: PMC5421865 DOI: 10.18632/oncotarget.15524] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2016] [Accepted: 02/06/2017] [Indexed: 12/12/2022] Open
Abstract
Mammalian Target of Rapamycin complex 2 (mTORC2) and its regulatory component Rapamycin-insensitive companion of mTOR (RICTOR) are increasingly recognized as important players in human cancer development and progression. However, the role of RICTOR in human pancreatic ductal adenocarcinoma (PDAC) is unclear so far. Here, we sought to analyze the effects of RICTOR inhibition in human pancreatic cancer cell lines in vitro and in vivo. Furthermore, RICTOR expression was determined in human PDAC samples. Results demonstrate that depletion of RICTOR with siRNA (transient knock-down) or shRNA (stable knock-down) has an inhibitory effect on tumor growth in vitro. Moreover, RICTOR inhibition led to impaired phosphorylation/activity of AGC kinases (AKT, SGK1). Interestingly, hypoxia-induced expression of hypoxia-induced factor-1α (HIF-1α) was diminished and secretion of vascular-endothelial growth factor-A (VEGF-A) was impaired upon targeting RICTOR. Stable RICTOR knock-down led to significant inhibition of tumor growth in subcutaneous and orthotopic tumor models which was accompanied by significant reduction of tumor cell proliferation. Finally, immunohistochemical analyses of 85 human PDAC samples revealed significantly poorer survival in patients with higher RICTOR expression. In conclusion, these findings provide first evidence for mTORC2/RICTOR as an attractive novel target for treatment of human PDAC.
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22
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Ku BM, Yi SY, Koh J, Bae YH, Sun JM, Lee SH, Ahn JS, Park K, Ahn MJ. The CDK4/6 inhibitor LY2835219 has potent activity in combination with mTOR inhibitor in head and neck squamous cell carcinoma. Oncotarget 2018; 7:14803-13. [PMID: 26909611 PMCID: PMC4924753 DOI: 10.18632/oncotarget.7543] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/23/2016] [Indexed: 01/07/2023] Open
Abstract
Deletion of CDKN2A (p16) or amplification of CCND1 (cyclin D1) occurs commonly in head and neck squamous cell carcinoma (HNSCC) and induces sustained cyclin-dependent kinase (CDK) 4/6 activation. Here, we report the antiproliferative activity of LY2835219, a selective CDK4/6 inhibitor through inhibition of CDK4/6-dependent Ser780 phosphorylation in retinoblastoma (RB) and induction of cell cycle arrest in HNSCC cells. In addition, we demonstrated the antitumor effects of HNSCC xenografts to LY2835219 in vivo. Given the limited effect in HNSCC as a single-agent treatment with LY2835219, a combinational strategy is required to enhance antitumor activity. At the molecular level, we found that LY2835219 inhibited activation of AKT and ERK, but not mTOR. The combination of LY2835219 with mTOR inhibitor was found to be more effective than either drug alone in vitro and in vivo. Taken together, our findings suggest that a combinational treatment with LY2835219 and mTOR inhibitor is a promising therapeutic approach for HNSCC.
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Affiliation(s)
- Bo Mi Ku
- Samsung Biomedical Research Institute, Seoul, Korea
| | - Seong Yoon Yi
- Division of Hematology-Oncology, Department of Internal Medicine, Inje University Ilsan Paik Hospital, Gyeonggi-do, Korea
| | - Jiae Koh
- Samsung Biomedical Research Institute, Seoul, Korea
| | - Yeon-Hee Bae
- Samsung Biomedical Research Institute, Seoul, Korea
| | - Jong-Mu Sun
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Se-Hoon Lee
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jin Seok Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Keunchil Park
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Myung-Ju Ahn
- Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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23
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Fong ELS, Toh TB, Lin QXX, Liu Z, Hooi L, Mohd Abdul Rashid MB, Benoukraf T, Chow EKH, Huynh TH, Yu H. Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer. Biomaterials 2018; 159:229-240. [PMID: 29353739 DOI: 10.1016/j.biomaterials.2017.12.026] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2017] [Revised: 12/21/2017] [Accepted: 12/31/2017] [Indexed: 12/28/2022]
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide, often manifesting at the advanced stage when cure is no longer possible. The discrepancy between preclinical findings and clinical outcome in HCC is well-recognized. So far, sorafenib is the only targeted therapy approved as first-line therapy for patients with advanced HCC. There is an urgent need for improved preclinical models for the development of HCC-targeted therapies. Patient-derived xenograft (PDX) tumor models have been shown to closely recapitulate human tumor biology and predict patient drug response. However, the use of PDX models is currently limited by high costs and low throughput. In this study, we engineered in vitro conditions conducive for the culture of HCC-PDX organoids derived from a panel of 14 different HCC-PDX lines through the use of a three-dimensional macroporous cellulosic sponge system. To validate the in vitro HCC-PDX models, both in vivo and in vitro HCC-PDX models were subjected to whole exome sequencing and RNA-sequencing. Correlative studies indicate strong concordance in genomic and transcriptomic profiles as well as intra-tumoral heterogeneity between each matched in vitro-in vivo HCC-PDX pairs. Furthermore, we demonstrate the feasibility of using these in vitro HCC-PDX models for drug testing, paving the way for more efficient preclinical studies in HCC drug development.
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Affiliation(s)
- Eliza Li Shan Fong
- Department of Biomedical Engineering, National University of Singapore, Singapore.
| | - Tan Boon Toh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Quy Xiao Xuan Lin
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Zheng Liu
- Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore
| | - Lissa Hooi
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | | | - Touati Benoukraf
- Cancer Science Institute of Singapore, National University of Singapore, Singapore
| | - Edward Kai-Hua Chow
- Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
| | | | - Hanry Yu
- Institute of Bioengineering and Nanotechnology, Agency for Science, Technology and Research (A*STAR), Singapore; Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Mechanobiology Institute, National University of Singapore, Singapore; BioSyM, Singapore-MIT Alliance for Research and Technology, Singapore; Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China; NUS Graduate School of Integrative Sciences and Engineering, National University of Singapore, Singapore
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24
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Abstract
Fibroblast growth factors (FGFs) and their receptors (FGFRs) regulate numerous cellular processes. Deregulation of FGFR signalling is observed in a subset of many cancers, making activated FGFRs a highly promising potential therapeutic target supported by multiple preclinical studies. However, early-phase clinical trials have produced mixed results with FGFR-targeted cancer therapies, revealing substantial complexity to targeting aberrant FGFR signalling. In this Review, we discuss the increasing understanding of the differences between diverse mechanisms of oncogenic activation of FGFR, and the factors that determine response and resistance to FGFR targeting.
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Affiliation(s)
- Irina S Babina
- Breast Cancer Now Research Centre, Institute of Cancer Research, London SW3 6JB, UK
| | - Nicholas C Turner
- Breast Cancer Now Research Centre, Institute of Cancer Research, London SW3 6JB, UK
- Breast Unit, The Royal Marsden Hospital, Fulham Road, London SW3 6JJ, UK
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25
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Ornitz DM, Legeai-Mallet L. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn 2017; 246:291-309. [PMID: 27987249 DOI: 10.1002/dvdy.24479] [Citation(s) in RCA: 142] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Revised: 12/04/2016] [Accepted: 12/05/2016] [Indexed: 12/11/2022] Open
Abstract
Autosomal dominant mutations in fibroblast growth factor receptor 3 (FGFR3) cause achondroplasia (Ach), the most common form of dwarfism in humans, and related chondrodysplasia syndromes that include hypochondroplasia (Hch), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia (TD). FGFR3 is expressed in chondrocytes and mature osteoblasts where it functions to regulate bone growth. Analysis of the mutations in FGFR3 revealed increased signaling through a combination of mechanisms that include stabilization of the receptor, enhanced dimerization, and enhanced tyrosine kinase activity. Paradoxically, increased FGFR3 signaling profoundly suppresses proliferation and maturation of growth plate chondrocytes resulting in decreased growth plate size, reduced trabecular bone volume, and resulting decreased bone elongation. In this review, we discuss the molecular mechanisms that regulate growth plate chondrocytes, the pathogenesis of Ach, and therapeutic approaches that are being evaluated to improve endochondral bone growth in people with Ach and related conditions. Developmental Dynamics 246:291-309, 2017. © 2016 Wiley Periodicals, Inc.
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Affiliation(s)
- David M Ornitz
- Department of Developmental Biology, Washington University School of Medicine, St. Louis, Missouri, USA
| | - Laurence Legeai-Mallet
- Imagine Institute, Inserm U1163, Université Paris Descartes, Service de Génétique, Hôpital Necker-Enfants Malades, AP-HP, Paris, France
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26
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Packer LM, Geng X, Bonazzi VF, Ju RJ, Mahon CE, Cummings MC, Stephenson SA, Pollock PM. PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2 mutant Endometrial Cancers. Mol Cancer Ther 2017; 16:637-648. [PMID: 28119489 DOI: 10.1158/1535-7163.mct-16-0415] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2016] [Revised: 12/01/2016] [Accepted: 01/04/2017] [Indexed: 11/16/2022]
Abstract
Improved therapeutic approaches are needed for the treatment of recurrent and metastatic endometrial cancer. Endometrial cancers display hyperactivation of the MAPK and PI3K pathways, the result of somatic aberrations in genes such as FGFR2, KRAS, PTEN, PIK3CA, and PIK3R1 The FGFR2 and PI3K pathways, have emerged as potential therapeutic targets in endometrial cancer. Activation of the PI3K pathway is seen in more than 90% of FGFR2mutant endometrial cancers. This study aimed to examine the efficacy of the pan-FGFR inhibitor BGJ398 with pan-PI3K inhibitors (GDC-0941, BKM120) and the p110α-selective inhibitor BYL719. We assessed synergy in three FGFR2mutant endometrial cancer cell lines (AN3CA, JHUEM2, and MFE296), and the combination of BGJ398 and GDC-0941 or BYL719 showed strong synergy. A significant increase in cell death and decrease in long-term survival was seen when PI3K inhibitors were combined with BGJ398. Importantly, these effects were seen at low concentrations correlating to only partial inhibition of AKT. The combination of BGJ398 and GDC-0941 showed tumor regressions in vivo, whereas each drug alone only showed moderate tumor growth inhibition. BYL719 alone resulted in increased tumor growth of AN3CA xenografts but in combination with BGJ398 resulted in tumor regression in both AN3CA- and JHUEM2-derived xenografts. These data provide evidence that subtherapeutic doses of PI3K inhibitors enhance the efficacy of anti-FGFR therapies, and a combination therapy may represent a superior therapeutic treatment in patients with FGFR2mutant endometrial cancer. Mol Cancer Ther; 16(4); 637-48. ©2017 AACR.
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Affiliation(s)
- Leisl M Packer
- Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia
| | - Xinyan Geng
- Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia
| | - Vanessa F Bonazzi
- Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia
| | - Robert J Ju
- Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia
| | - Clare E Mahon
- Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia
| | - Margaret C Cummings
- School of Medicine, University of Queensland Centre for Clinical Research, Queensland, Australia
| | - Sally-Anne Stephenson
- Eph Receptor Biology Group, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia
| | - Pamela M Pollock
- Endometrial Cancer Laboratory, Queensland University of Technology (QUT), Translational Research Institute, Queensland, Australia.
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27
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Samonakis DN, Kouroumalis EA. Systemic treatment for hepatocellular carcinoma: Still unmet expectations. World J Hepatol 2017; 9:80-90. [PMID: 28144389 PMCID: PMC5241532 DOI: 10.4254/wjh.v9.i2.80] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2016] [Revised: 10/14/2016] [Accepted: 11/22/2016] [Indexed: 02/06/2023] Open
Abstract
Many patients with hepatocellular carcinoma (HCC) are diagnosed in an advanced stage, so they cannot be offered the option of curative treatments. The results of systemic chemotherapy are unsatisfactory and this has led to molecular targeted approaches. HCC develops in chronically damaged tissue due to cirrhosis in most patients. Several different cell types and molecules constitute a unique microenvironment in the liver, which has significant implications in tumor development and invasion. This, together with genome instability, contributes to a significant heterogeneity which is further enhanced by the molecular differences of the underlying causes. New classifications based on genetic characteristics of the tissue microenvironment have been proposed and key carcinogenic signaling pathways have been described. Tumor and adjacent tissue profiling seem biologically promising, but have not yet been translated into clinical settings. The encouraging first results with molecular - genetic signatures should be validated and clinically applicable. A more personalized approach to modern management of HCC is urgently needed.
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28
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The role of regulatory B cells (Bregs) in the Tregs-amplifying effect of Sirolimus. Int Immunopharmacol 2016; 38:90-6. [DOI: 10.1016/j.intimp.2016.05.014] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2015] [Revised: 05/16/2016] [Accepted: 05/17/2016] [Indexed: 02/03/2023]
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29
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Komla-Ebri D, Dambroise E, Kramer I, Benoist-Lasselin C, Kaci N, Le Gall C, Martin L, Busca P, Barbault F, Graus-Porta D, Munnich A, Kneissel M, Di Rocco F, Biosse-Duplan M, Legeai-Mallet L. Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model. J Clin Invest 2016; 126:1871-84. [PMID: 27064282 DOI: 10.1172/jci83926] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2015] [Accepted: 02/25/2016] [Indexed: 01/08/2023] Open
Abstract
Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH.
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30
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Thillai K, Ross P, Sarker D. Molecularly targeted therapy for advanced hepatocellular carcinoma - a drug development crisis? World J Gastrointest Oncol 2016; 8:173-85. [PMID: 26909132 PMCID: PMC4753168 DOI: 10.4251/wjgo.v8.i2.173] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2015] [Revised: 11/16/2015] [Accepted: 12/09/2015] [Indexed: 02/05/2023] Open
Abstract
Hepatocellular carcinoma is the fastest growing cause of cancer related death globally. Sorafenib, a multi-targeted kinase inhibitor, is the only drug proven to improve outcomes in patients with advanced disease offering modest survival benefit. Although comprehensive genomic mapping has improved understanding of the genetic aberrations in hepatocellular cancer (HCC), this knowledge has not yet impacted clinical care. The last few years have seen the failure of several first and second line phase III clinical trials of novel molecularly targeted therapies, warranting a change in the way new therapies are investigated in HCC. Potential reasons for these failures include clinical and molecular heterogeneity, trial design and a lack of biomarkers. This review discusses the current crisis in HCC drug development and how we should learn from recent trial failures to develop a more effective personalised treatment paradigm for patients with HCC.
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31
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Malley CO, Pidgeon GP. The mTOR pathway in obesity driven gastrointestinal cancers: Potential targets and clinical trials. BBA CLINICAL 2015; 5:29-40. [PMID: 27051587 PMCID: PMC4802403 DOI: 10.1016/j.bbacli.2015.11.003] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/12/2015] [Revised: 11/03/2015] [Accepted: 11/11/2015] [Indexed: 12/20/2022]
Abstract
The mechanistic target of rapamycin (mTOR) is a crucial point of convergence between growth factor signalling, metabolism, nutrient status and cellular proliferation. The mTOR pathway is heavily implicated in the progression of many cancers and is emerging as an important driver of gastrointestinal (GI) malignancies. Due to its central role in adapting metabolism to environmental conditions, mTOR signalling is also believed to be critical in the development of obesity. Recent research has delineated that excessive nutrient intake can promote signalling through the mTOR pathway and possibly evoke changes to cellular metabolism that could accelerate obesity related cancers. Acting through its two effector complexes mTORC1 and mTORC2, mTOR dictates the transcription of genes important in glycolysis, lipogenesis, protein translation and synthesis and has recently been defined as a central mediator of the Warburg effect in cancer cells. Activation of the mTOR pathway is involved in both the pathogenesis of GI malignancies and development of resistance to conventional chemotherapy and radiotherapy. The use of mTOR inhibitors is a promising therapeutic option in many GI malignancies, with greatest clinical efficacy seen in combination regimens. Recent research has also provided insight into crosstalk between mTOR and other pathways which could potentially expand the list of therapeutic targets in the mTOR pathway. Here we review the available strategies for targeting the mTOR pathway in GI cancers. We discuss current clinical trials of both established and novel mTOR inhibitors, with particular focus on combinations of these drugs with conventional chemotherapy, radiotherapy and targeted therapies.
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Affiliation(s)
- Cian O Malley
- Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
| | - Graham P Pidgeon
- Department of Surgery, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland
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32
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Schmidt B, Wei L, DePeralta DK, Hoshida Y, Tan PS, Sun X, Sventek JP, Lanuti M, Tanabe KK, Fuchs BC. Molecular subclasses of hepatocellular carcinoma predict sensitivity to fibroblast growth factor receptor inhibition. Int J Cancer 2015; 138:1494-505. [PMID: 26481559 DOI: 10.1002/ijc.29893] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 08/26/2015] [Accepted: 09/10/2015] [Indexed: 01/02/2023]
Abstract
A recent gene expression classification of hepatocellular carcinoma (HCC) includes a poor survival subclass termed S2 representing about one-third of all HCC in clinical series. S2 cells express E-cadherin and c-myc and secrete AFP. As the expression of fibroblast growth factor receptors (FGFRs) differs between S2 and non-S2 HCC, this study investigated whether molecular subclasses of HCC predict sensitivity to FGFR inhibition. S2 cell lines were significantly more sensitive (p < 0.001) to the FGFR inhibitors BGJ398 and AZD4547. BGJ398 decreased MAPK signaling in S2 but not in non-S2 cell lines. All cell lines expressed FGFR1 and FGFR2, but only S2 cell lines expressed FGFR3 and FGFR4. FGFR4 siRNA decreased proliferation by 44% or more in all five S2 cell lines (p < 0.05 for each cell line), a significantly greater decrease than seen with knockdown of FGFR1-3 with siRNA transfection. FGFR4 knockdown decreased MAPK signaling in S2 cell lines, but little effect was seen with knockdown of FGFR1-3. In conclusion, the S2 molecular subclass of HCC is sensitive to FGFR inhibition. FGFR4-MAPK signaling plays an important role in driving proliferation of a molecular subclass of HCC. This classification system may help to identify those patients who are most likely to benefit from inhibition of this pathway.
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Affiliation(s)
- Benjamin Schmidt
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
| | - Lan Wei
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
| | - Danielle K DePeralta
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
| | - Yujin Hoshida
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Poh Seng Tan
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.,Division of Gastroenterology and Hepatology, University Medicine Cluster, National University Health System, Singapore, Singapore
| | - Xiaochen Sun
- Liver Cancer Program, Tisch Cancer Institute, Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Janelle P Sventek
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
| | - Michael Lanuti
- Division of Thoracic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA
| | - Kenneth K Tanabe
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
| | - Bryan C Fuchs
- Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA
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33
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Ye Y, Jiang D, Li J, Wang M, Han C, Zhang X, Zhao C, Wen J, Kan Q. Silencing of FGFR4 could influence the biological features of gastric cancer cells and its therapeutic value in gastric cancer. Tumour Biol 2015; 37:3185-95. [PMID: 26432329 DOI: 10.1007/s13277-015-4100-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 09/14/2015] [Indexed: 12/29/2022] Open
Abstract
To clarify the role of fibroblast growth factor receptor 4 (FGFR4) in gastric cancer (GC) and explore the therapeutic value of BGJ398 targeted to FGFR4. We constructed lentivirus vectors to stably knockdown FGFR4 expression in GC cells. Function assays in vitro and in vivo, treated with 5-fluorouracil (5-Fu) and BGJ398, were performed to study the change of biological behaviors of GC cells and related mechanism. The proliferation and invasive ability of HGC27 and MKN45 significantly decreased while the apoptosis rate of GC cells obviously increased in shRNA group (P < 0.05). The expressions of Bcl-xl, FLIP, PCNA, vimentin, p-erk, and p-STAT3 significantly reduced while the expressions of caspase-3 and E-cadherin markly enhanced in shRNA group. The proliferation abilities of GC cells were more significantly inhibited by the combination of BGJ398 and 5-Fu in shRNA group (P < 0.05). Compared to negative control (NC), the single and combination of 5-Fu and BGJ398 all significantly increased the apoptosis rate of GC cells, especially in the combination group (P < 0.01). The single and combination of 5-Fu and BGJ398 decreased the expressions of PCNA, Bcl-xl, and FLIP while increased the expression of caspase-3 in GC cells, especially in shRNA groups. Furthermore, knockdown of FGFR4 expression might prevent the growth of GC in vivo. Silencing of FGFR4 expression could weaken the invasive ability, increase the apoptosis rate, and decrease the proliferation ability of GC cells in vitro and in vivo. Furthermore, the combination of 5-Fu and BGJ398 had synergy in inhibiting the proliferation ability and increasing apoptosis rate of GC cells, directing a new target drug in GC.
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Affiliation(s)
- Yanwei Ye
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China. .,Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
| | - Dongbao Jiang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jingjing Li
- Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Min Wang
- Department of Function, The Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chao Han
- Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiefu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunlin Zhao
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jianguo Wen
- Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Quancheng Kan
- Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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