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Guo J, Chen X, Li X, Wang X, Shao M, Song X, Zhang L, Huang S, Patterson AV, Smaill JB, Zhou Y, Yu X, Chen Y, Lu X. Optimization of Aminoindazole derivatives as highly selective covalent inhibitors for wild-type and mutant FGFR4. Bioorg Chem 2025; 160:108469. [PMID: 40252369 DOI: 10.1016/j.bioorg.2025.108469] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2025] [Revised: 04/04/2025] [Accepted: 04/11/2025] [Indexed: 04/21/2025]
Abstract
The Fibroblast growth factor receptor 4 (FGFR4) has emerged as a potential oncogenic driver in hepatocellular carcinoma (HCC), primarily due to aberrations in the FGFR4-FGF19 signaling axis. Although the FGFR4-selective inhibitors have been reported, none have received approval. Further, the clinical acquired resistance caused by FGFR4 mutations has become an unmet clinical need for cancer therapy. In this study, we designed and synthesized a series of 3-amido-1H-indazole-based FGFR4 irreversible inhibitors, targeting both wild-type FGFR4 and the gatekeeper and molecular brake mutants. The representative compound, 48c, exhibited potent inhibitory activity against FGFR4WT kinase (IC50 = 2.9 nM) and picomolar activity against FGFR4WT, FGFR4V550L, and FGFR4V550M-driven Ba/F3 cell lines (IC50 < 0.1, 0.3, and 0.3 nM, respectively). 48c exhibited high selectivity across a panel of 66 kinases harboring a cysteine at the hinge region, highlighting its potential as a promising therapeutic candidate for overcoming resistance in FGFR4-associated tumors.
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Affiliation(s)
- Jing Guo
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaojuan Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Xiaofei Li
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xuan Wang
- Guangdong Second Provincial General Hospital, Postdoctoral Research Station of Traditional Chinese Medicine, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Min Shao
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiaojuan Song
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Lin Zhang
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Shengjie Huang
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Adam V Patterson
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 92019, New Zealand
| | - Jeff B Smaill
- Auckland Cancer Society Research Centre, Faculty of Medical and Health Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, The University of Auckland, Auckland 92019, New Zealand
| | - Yang Zhou
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China
| | - Xiangrong Yu
- Department of Radiology, Zhuhai People's Hospital, Zhuhai Hospital affiliated with Jinan University, Zhuhai 519000, China.
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China.
| | - Xiaoyun Lu
- State Key Laboratory of Bioactive Molecules and Druggability Assessment, International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education, Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou 510632, China.
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Wu X, Pan J, Fan R, Zhang Y, Wang C, Wang G, Liu J, Cui M, Yue J, Jin R, Duan Z, Zheng M, Mei L, Zhou L, Tan M, Ai J, Lu X. Residue-Selective Inhibitors Discovery via Covalent DNA-Encoded Chemical Libraries with Diverse Warheads. J Am Chem Soc 2025; 147:15469-15481. [PMID: 40292872 DOI: 10.1021/jacs.5c01712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/30/2025]
Abstract
Covalent small molecule drugs have emerged as a crucial support in precision therapy due to their high selectivity and robust potency. Covalent DNA-encoded chemical library (CoDEL) technology is an advanced platform for covalent drug discovery. However, the application of CoDELs is constrained by a single-residue focus and limited warhead diversity. Here we report a method to identify residue-selective inhibitors using CoDELs with diverse warheads targeting multiple distinct residues. We systematically evaluated the reactivity of 17 warheads with 9 nucleophilic amino acids of FGFR2 and then constructed CoDELs comprising 24.8 million compounds. These CoDELs enabled the identification of active covalent inhibitors targeting cysteine, lysine, arginine, or glutamic acid. The lysine-targeting inhibitor engaged a novel reactive site. The arginine-targeting inhibitor demonstrated subtype selectivity and overcame drug resistance. The glutamic acid-targeting inhibitor validated the druggability of this unconventional covalent residue site. These findings suggest that our work could potentially expand the target space of covalent drugs and promote precision therapy by harnessing the power of the CoDELs.
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Affiliation(s)
- Xinyuan Wu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Jiayi Pan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Rufeng Fan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Yiwei Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Chao Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Guoliang Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 138 Xianlin Road, Nanjing 210023, China
| | - Jiaxiang Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Mengqing Cui
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jinfeng Yue
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Rui Jin
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Zhiqiang Duan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Mingyue Zheng
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
| | - Lianghe Mei
- Suzhou Institute of Materia Medica, Suzhou, Jiangsu 215123, China
| | - Lu Zhou
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Minjia Tan
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
- Zhongshan Institute for Drug Discovery, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Zhongshan 528400, China
| | - Jing Ai
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
- Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong 264117, China
| | - Xiaojie Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China
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Yang D, Lyu C, He K, Pang K, Guo Z, Wu D. Bile Acid Diarrhea: From Molecular Mechanisms to Clinical Diagnosis and Treatment in the Era of Precision Medicine. Int J Mol Sci 2024; 25:1544. [PMID: 38338820 PMCID: PMC10855108 DOI: 10.3390/ijms25031544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/18/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Bile acid diarrhea (BAD) is a multifaceted intestinal disorder involving intricate molecular mechanisms, including farnesoid X receptor (FXR), fibroblast growth factor receptor 4 (FGFR4), and Takeda G protein-coupled receptor 5 (TGR5). Current diagnostic methods encompass bile acid sequestrants (BAS), 48-h fecal bile acid tests, serum 7α-hydroxy-4-cholesten-3-one (C4), fibroblast growth factor 19 (FGF19) testing, and 75Selenium HomotauroCholic acid test (75SeHCAT). Treatment primarily involves BAS and FXR agonists. However, due to the limited sensitivity and specificity of current diagnostic methods, as well as suboptimal treatment efficacy and the presence of side effects, there is an urgent need to establish new diagnostic and treatment methods. While prior literature has summarized various diagnostic and treatment methods and the pathogenesis of BAD, no previous work has linked the two. This review offers a molecular perspective on the clinical diagnosis and treatment of BAD, with a focus on FXR, FGFR4, and TGR5, emphasizing the potential for identifying additional molecular mechanisms as treatment targets and bridging the gap between diagnostic and treatment methods and molecular mechanisms for a novel approach to the clinical management of BAD.
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Affiliation(s)
- Daiyu Yang
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (D.Y.); (K.P.); (Z.G.)
| | - Chengzhen Lyu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (C.L.); (K.H.)
| | - Kun He
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (C.L.); (K.H.)
| | - Ke Pang
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (D.Y.); (K.P.); (Z.G.)
| | - Ziqi Guo
- Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (D.Y.); (K.P.); (Z.G.)
| | - Dong Wu
- State Key Laboratory of Complex Severe and Rare Diseases, Department of Gastroenterology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China; (C.L.); (K.H.)
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Liu B, Ding J, Liu Y, Wu J, Wu X, Chen Q, Li W. Elucidating the potential effects of point mutations on FGFR3 inhibitor resistance via combined molecular dynamics simulation and community network analysis. J Comput Aided Mol Des 2023; 37:325-338. [PMID: 37269435 DOI: 10.1007/s10822-023-00510-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 05/23/2023] [Indexed: 06/05/2023]
Abstract
FGFR3 kinase mutations are associated with a variety of malignancies, but FGFR3 mutant inhibitors have rarely been studied. Furthermore, the mechanism of pan-FGFR inhibitors resistance caused by kinase domain mutations is still unclear. In this study, we try to explain the mechanism of drug resistance to FGFR3 mutation through global analysis and local analysis based on molecular dynamics simulation, binding free energy analysis, umbrella sampling and community network analysis. The results showed that FGFR3 mutations caused a decrease in the affinity between drugs and FGFR3 kinase, which was consistent with the reported experimental results. Possible mechanisms are that mutations affect drug-protein affinity by altering the environment of residues near the hinge region where the protein binds to the drug, or by affecting the A-loop and interfering with the allosteric communication networks. In conclusion, we systematically elucidated the underlying mechanism of pan-FGFR inhibitor resistance caused by FGFR3 mutation based on molecular dynamics simulation strategy, which provided theoretical guidance for the development of FGFR3 mutant kinase inhibitors.
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Affiliation(s)
- Bo Liu
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Juntao Ding
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yugang Liu
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jianzhang Wu
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
- The Eye Hospital, School of Ophthalmology & Optometry, Wenzhou Medical University, Wenzhou, 325027, China
| | - Xiaoping Wu
- Institute of Tissue Transplantation and Immunology, College of Life Science and Technology, Jinan University, Guangzhou, 510632, China
- MOE Key Laboratory of Tumor Molecular Biology, Jinan University, Guangzhou, 510632, China
| | - Qian Chen
- Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, 314102, China.
| | - Wulan Li
- The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
- Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, Zhejiang, 325000, China.
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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Xu J, Cui J, Jiang H, Zeng Y, Cong X. Phase 1 dose escalation study of FGFR4 inhibitor in combination with pembrolizumab in advanced solid tumors patients. Cancer Med 2023; 12:7762-7771. [PMID: 36622048 PMCID: PMC10134273 DOI: 10.1002/cam4.5532] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 12/01/2022] [Indexed: 01/10/2023] Open
Abstract
OBJECTIVE Inhibition of fibroblast growth factor (FGF) 19-FGF Receptor 4 (FGFR4) signaling demonstrates potent anticancer activity. EVER4010001 is a highly selective FGFR4 inhibitor and pembrolizumab is approved for the treatment of several solid tumors. This study determined the maximum tolerated dose (MTD), recommended Phase 2 dose (RP2D), pharmacokinetics, safety, and preliminary efficacy of EVER4010001 plus pembrolizumab in patients with advanced solid tumors. METHODS This Phase 1, multicenter, open-label study enrolled 19 Asian-Chinese patients (57.9% male: median age 58 years) with advanced solid tumors. For "3+3" dose escalation, 3-6 patients received treatment at each dose level (EVER4010001 40, 60, 80, or 100 mg twice daily [BID] plus pembrolizumab 200 mg every 3 weeks). RESULTS At the data cutoff (August 12, 2021), no dose-limiting toxicities (DLTs) were reported at 40 mg-80 mg. At 100 mg, 2 (40.0%) patients had 3 DLTs within the 28-day DLT observation period after first administration. Median time to peak EVER4010001 concentration (Tmax ) was 0.55-1.03 hours. Mean terminal EVER4010001 half-life (T1/2 ) was 4.00-4.92 hours. The area under the concentration-time curve (AUC0-t ) and maximum observed concentration (Cmax ) ranged from 2370.87-5475.77 hour*ng/ml and 606.07-1348.86 ng/ml, respectively. The most common EVER4010001-related treatment-emergent adverse events were diarrhea (94.7%), increased aspartate aminotransferase (57.9%), and increased alanine aminotransferase (47.4%). CONCLUSION Eighty milligrams BID was the MTD and RP2D for EVER4010001 plus pembrolizumab. Efficacy results were promising, and no new safety risks were reported, justifying the Phase 2 portion of this study.
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Affiliation(s)
- Jianming Xu
- Oncology Department, Chinese PLA General Hospital, Beijing, China
| | - Jiuwei Cui
- Oncology Department, The First Hospital of Jilin University, Changchun, China
| | - Haiping Jiang
- Oncology Department, The First Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yan Zeng
- EverNov Medicines (Zhuhai Hengqin) Co., Ltd, Zhuhai, China
| | - Xiuyu Cong
- EverNov Medicines (Zhuhai Hengqin) Co., Ltd, Zhuhai, China
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Wilbaux M, Yang S, Jullion A, Demanse D, Porta DG, Myers A, Meille C, Gu Y. Integration of Pharmacokinetics, Pharmacodynamics, Safety, and Efficacy into Model-Informed Dose Selection in Oncology First-in-Human Study: A Case of Roblitinib (FGF401). Clin Pharmacol Ther 2022; 112:1329-1339. [PMID: 36131557 DOI: 10.1002/cpt.2752] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 09/09/2022] [Indexed: 01/31/2023]
Abstract
Model-informed dose selection has been drawing increasing interest in oncology early clinical development. The current paper describes the example of FGF401, a selective fibroblast growth factor receptor 4 (FGFR4) inhibitor, in which a comprehensive modeling and simulation (M&S) framework, using both pharmacometrics and statistical methods, was established during its first-in-human clinical development using the totality of pharmacokinetics (PK), pharmacodynamic (PD) biomarkers, and safety and efficacy data in patients with cancer. These M&S results were used to inform FGF401 dose selection for future development. A two-compartment population PK (PopPK) model with a delayed 0-order absorption and linear elimination adequately described FGF401 PK. Indirect PopPK/PD models including a precursor compartment were independently established for two biomarkers: circulating FGF19 and 7α-hydroxy-4-cholesten-3-one (C4). Model simulations indicated a close-to-maximal PD effect achieved at the clinical exposure range. Time-to-progression was analyzed by Kaplan-Meier method which favored a trough concentration (Ctrough )-driven efficacy requiring Ctrough above a threshold close to the drug concentration producing 90% inhibition of phospho-FGFR4. Clinical tumor growth inhibition was described by a PopPK/PD model that reproduced the dose-dependent effect on tumor growth. Exposure-safety analyses on the expected on-target adverse events, including elevation of aspartate aminotransferase and diarrhea, indicated a lack of clinically relevant relationship with FGF401 exposure. Simulations from an indirect PopPK/PD model established for alanine aminotransferase, including a chain of three precursor compartments, further supported that maximal target inhibition was achieved and there was a lack of safety-exposure relationship. This M&S framework supported a dose selection of 120 mg once daily fasted or with a low-fat meal and provides a practical example that might be applied broadly in oncology early clinical development.
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Affiliation(s)
| | - Shu Yang
- Pharmacometrics, Novartis, East Hanover, New Jersey, USA
| | - Astrid Jullion
- Early Development Analytics, Novartis, Basel, Switzerland
| | - David Demanse
- Early Development Analytics, Novartis, Basel, Switzerland
| | - Diana Graus Porta
- Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Andrea Myers
- Global Drug Development, Novartis, East Hanover, New Jersey, USA
| | | | - Yi Gu
- Pharmacokinetic Sciences, Translational Medicine, Novartis, Cambridge, Massachusetts, USA
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Walden D, Eslinger C, Bekaii-Saab T. Pemigatinib for adults with previously treated, locally advanced or metastatic cholangiocarcinoma with FGFR2 fusions/rearrangements. Therap Adv Gastroenterol 2022; 15:17562848221115317. [PMID: 35967919 PMCID: PMC9364186 DOI: 10.1177/17562848221115317] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/06/2022] [Indexed: 02/04/2023] Open
Abstract
Biliary tract cancers are a diverse and aggressive malignancy that carry a poor chance for curative treatment and significant associated mortality. Current first-line treatment only extends median overall survival to roughly 1 year and is associated with a significant adverse event profile. Recently, advancements in genetic sequencing have opened new avenues of targeted treatment. In cholangiocarcinoma, FGFR2 alterations have been shown to be present in roughly 10-15% of intrahepatic cholangiocarcinoma. Pemigatinib, a FGFR1-4 inhibitor, has been shown to significantly extend survival in the second-line setting to over 20 months in patients who harbor FGFR2 fusions. Here, we outline the development and future direction of pemigatinib and other FGFR2 inhibitors in the field of advanced biliary tract cancers.
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Pan C, Nie W, Wang J, Du J, Pan Z, Gao J, Lu Y, Che J, Zhu H, Dai H, Chen B, He Q, Dong X. Design, synthesis and biological evaluation of quinazoline derivatives as potent and selective FGFR4 inhibitors. Eur J Med Chem 2021; 225:113794. [PMID: 34488024 DOI: 10.1016/j.ejmech.2021.113794] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 11/27/2022]
Abstract
Aberrant activation of the fibroblast growth factor 19-fibroblast growth factor receptor 4 (FGF19-FGFR4) signaling pathway has been proved to promote hepatocellular carcinoma (HCC) proliferation. It is assumed that the first FGFR4 inhibitor BLU9931 did not enter clinical studies, presumably due to its rapid metabolism in liver microsomes. Here, we report the development of series of quinazoline derivatives based on FGFR4 inhibitor BLU9931 through structural modification of its solvent region pocket to minimize its potential metabolic liability. Among them, compound 35a exhibited comparable or superior kinase inhibitory activity (IC50 = 8.5 nM) and selectivity in cells. More importantly, compound 35a improved liver microsomes stability compared to BLU9931. Cellular mechanistic studies demonstrated that 35a induced apoptosis via the FGFR4 signaling pathway blockage. In addition, the computational simulation revealed the possible binding mode to FGFR4 protein, which provides a plausible explanation of high potent and metabolic stability.
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Affiliation(s)
- Chenghao Pan
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Wenwen Nie
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jiao Wang
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jiamin Du
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Zhichao Pan
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jian Gao
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Yang Lu
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Jinxin Che
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Hong Zhu
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China
| | - Haibin Dai
- Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China
| | - Binhui Chen
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China.
| | - Qiaojun He
- Institute of Pharmacology & Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China.
| | - Xiaowu Dong
- Hangzhou Institute of Innovative Medicine, Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, PR China; Department of Pharmacy, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou, 310018, PR China; Cancer Center, Zhejiang University, Hangzhou, 310058, PR China.
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9
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Dark and bright side of targeting fibroblast growth factor receptor 4 in the liver. J Hepatol 2021; 75:1440-1451. [PMID: 34364916 DOI: 10.1016/j.jhep.2021.07.029] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Revised: 07/09/2021] [Accepted: 07/26/2021] [Indexed: 12/12/2022]
Abstract
Fibroblast growth factor (FGF) receptor 4 (FGFR4) and its cognate ligand, FGF19, are implicated in a range of cellular processes, including differentiation, metabolism and proliferation. Indeed, their aberrant activation has been associated with the development of hepatic tumours. Despite great advances in early diagnosis and the development of new therapies, liver cancer is still associated with a high mortality rate, owing primarily to high molecular heterogeneity and unclear molecular targeting. The development of FGFR4 inhibitors is a promising tool in patients with concomitant supraphysiological levels of FGF19 and several clinical trials are testing these treatments for patients with advanced hepatocellular carcinoma (HCC). Conversely, using FGF19 analogues to activate FGFR4-KLOTHO β represents a novel therapeutic strategy in patients presenting with cholestatic liver disorders and non-alcoholic steatohepatitis, which could potentially prevent the development of metabolic HCC. Herein, we provide an overview of the currently available therapeutic options for targeting FGFR4 in HCC and other liver diseases, highlighting the need to carefully stratify patients and personalise therapeutic strategies.
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10
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Liu Y, Wang C, Li J, Zhu J, Zhao C, Xu H. Novel Regulatory Factors and Small-Molecule Inhibitors of FGFR4 in Cancer. Front Pharmacol 2021; 12:633453. [PMID: 33981224 PMCID: PMC8107720 DOI: 10.3389/fphar.2021.633453] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/05/2021] [Indexed: 01/02/2023] Open
Abstract
Fibroblast growth factor receptor 4 (FGFR4) is a tyrosine kinase receptor that is a member of the fibroblast growth factor receptor family and is stimulated by highly regulated ligand binding. Excessive expression of the receptor and its ligand, especially FGF19, occurs in many types of cancer. Abnormal FGFR4 production explains these cancer formations, and therefore, this receptor has emerged as a potential target for inhibiting cancer development. This review discusses the diverse mechanisms of oncogenic activation of FGFR4 and highlights some currently available inhibitors targeting FGFR4.
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Affiliation(s)
- Yanan Liu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Canwei Wang
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jifa Li
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Jiandong Zhu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
| | - Chengguang Zhao
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Huanhai Xu
- Affiliated Yueqing Hospital, Wenzhou Medical University, Wenzhou, China
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11
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Wang H, Yang J, Zhang K, Liu J, Li Y, Su W, Song N. Advances of Fibroblast Growth Factor/Receptor Signaling Pathway in Hepatocellular Carcinoma and its Pharmacotherapeutic Targets. Front Pharmacol 2021; 12:650388. [PMID: 33935756 PMCID: PMC8082422 DOI: 10.3389/fphar.2021.650388] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 03/11/2021] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a type of primary liver cancer with poor prognosis, and its incidence and mortality rate are increasing worldwide. It is refractory to conventional chemotherapy and radiotherapy owing to its high tumor heterogeneity. Accumulated genetic alterations and aberrant cell signaling pathway have been characterized in HCC. The fibroblast growth factor (FGF) family and their receptors (FGFRs) are involved in diverse biological activities, including embryonic development, proliferation, differentiation, survival, angiogenesis, and migration, etc. Data mining results of The Cancer Genome Atlas demonstrate high levels of FGF and/or FGFR expression in HCC tumors compared with normal tissues. Moreover, substantial evidence indicates that the FGF/FGFR signaling axis plays an important role in various mechanisms that contribute to HCC development. At present, several inhibitors targeting FGF/FGFR, such as multikinase inhibitors, specific FGFR4 inhibitors, and FGF ligand traps, exhibit antitumor activity in preclinical or early development phases in HCC. In this review, we summarize the research progress regarding the molecular implications of FGF/FGFR-mediated signaling and the development of FGFR-targeted therapeutics in hepatocarcinogenesis.
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Affiliation(s)
- Haijun Wang
- Key Laboratory of Clinical Molecular Pathology, Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China.,School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jie Yang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Ke Zhang
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Jia Liu
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China
| | - Yushan Li
- School of Public Health, Xinxiang Medical University, Xinxiang, China
| | - Wei Su
- Key Laboratory of Clinical Molecular Pathology, Department of Pathology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, China
| | - Na Song
- School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, China.,Institute of Precision Medicine, Xinxiang Medical University, Xinxiang, China
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12
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Wang J, Zhao H, Zheng L, Zhou Y, Wu L, Xu Y, Zhang X, Yan G, Sheng H, Xin R, Jiang L, Lei J, Zhang J, Chen Y, Peng J, Chen Q, Yang S, Yu K, Li D, Xie Q, Li Y. FGF19/SOCE/NFATc2 signaling circuit facilitates the self-renewal of liver cancer stem cells. Am J Cancer Res 2021; 11:5045-5060. [PMID: 33754043 PMCID: PMC7978301 DOI: 10.7150/thno.56369] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/31/2021] [Indexed: 02/07/2023] Open
Abstract
Background & Aims: Liver cancer stem cells (LCSCs) mediate therapeutic resistance and correlate with poor outcomes in patients with hepatocellular carcinoma (HCC). Fibroblast growth factor (FGF)-19 is a crucial oncogenic driver gene in HCC and correlates with poor prognosis. However, whether FGF19 signaling regulates the self-renewal of LCSCs is unknown. Methods: LCSCs were enriched by serum-free suspension. Self-renewal of LCSCs were characterized by sphere formation assay, clonogenicity assay, sorafenib resistance assay and tumorigenic potential assays. Ca2+ image was employed to determine the intracellular concentration of Ca2+. Gain- and loss-of function studies were applied to explore the role of FGF19 signaling in the self-renewal of LCSCs. Results: FGF19 was up-regulated in LCSCs, and positively correlated with certain self-renewal related genes in HCC. Silencing FGF19 suppressed self-renewal of LCSCs, whereas overexpressing FGF19 facilitated CSCs-like properties via activation of FGF receptor (FGFR)-4 in none-LCSCs. Mechanistically, FGF19/FGFR4 signaling stimulated store-operated Ca2+ entry (SOCE) through both the PLCγ and ERK1/2 pathways. Subsequently, SOCE-calcineurin signaling promoted the activation and translocation of nuclear factors of activated T cells (NFAT)-c2, which transcriptionally activated the expression of stemness-related genes (e.g., NANOG, OCT4 and SOX2), as well as FGF19. Furthermore, blockade of FGF19/FGFR4-NFATc2 signaling observably suppressed the self-renewal of LCSCs. Conclusions: FGF19/FGFR4 axis promotes the self-renewal of LCSCs via activating SOCE/NFATc2 pathway; in turn, NFATc2 transcriptionally activates FGF19 expression. Targeting this signaling circuit represents a potential strategy for improving the therapeutic efficacy of HCC.
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13
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Huynh H, Prawira A, Le TBU, Vu TC, Hao HX, Huang A, Wang Y, Porta DG. FGF401 and vinorelbine synergistically mediate antitumor activity and vascular normalization in FGF19-dependent hepatocellular carcinoma. Exp Mol Med 2020; 52:1857-1868. [PMID: 33235319 PMCID: PMC8080677 DOI: 10.1038/s12276-020-00524-4] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 09/10/2020] [Accepted: 09/15/2020] [Indexed: 01/01/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal cancer with limited therapeutic options, and standard therapy with sorafenib provides only modest survival benefits. Fibroblast growth factor 19 (FGF19) has been proposed as a driver oncogene, and targeting its receptor, FGFR-4, may provide a better alternative to standard therapy for patients with FGF19-driven tumors. Sixty-three HCC patient-derived xenograft (PDX) models were screened for FGF19 expression. Mice bearing high and low FGF19-expressing tumors were treated with FGF401 and/or vinorelbine, and the antitumor activity of both agents was assessed individually and in combination. Tumor vasculature and intratumoral hypoxia were also examined. High FGF19 expression was detected in 14.3% (9 of 63) of the HCC models tested and may represent a good target for HCC treatment. FGF401 potently inhibited the growth of high FGF19-expressing HCC models regardless of FGF19 gene amplification. Furthermore, FGF401 inhibited the FGF19/FGFR-4 signaling pathway, cell proliferation, and hypoxia, induced apoptosis and blood vessel normalization and prolonged the overall survival (OS) of mice bearing high FGF19 tumors. FGF401 synergistically acted with the microtubule-depolymerizing drug vinorelbine to further suppress tumor growth, promote apoptosis, and prolong the OS of mice bearing high FGF19 tumors, with no evidence of increased toxicity. Our study suggests that a subset of patients with high FGF19-expressing HCC tumors could benefit from FGF401 or FGF401/vinorelbine treatment. A high level of FGF19 in a tumor may serve as a potential biomarker for patient selection. The drugs FGF401 and vinorelbine, when working together synergistically, could be effective in treating those liver cancers driven by the activity of the fibroblast growth factor 19 (FGF19) protein. The drugs’ effects on human tumors grafted into mice were studied by an international research team led by Hung Huynh at the National Cancer Centre in Singapore. FGF401 is a small molecule that inhibits the activity of the receptor protein that the FGF19 growth factor interacts with to promote some cancers. Vinorelbine disrupts protein microtubules required for the cell division that allows cancer cells to multiply. In combination, the drugs achieved significantly enhanced anti-cancer effects which can now be tested in clinical trials. The research also uncovered new details of FGF401’s therapeutic actions, including its ability to restore healthy blood vessel formation.
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Affiliation(s)
- Hung Huynh
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Singapore, Singapore.
| | - Aldo Prawira
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Singapore, Singapore
| | - Thi Bich Uyen Le
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Singapore, Singapore
| | - Thanh Chung Vu
- Laboratory of Molecular Endocrinology, Division of Molecular and Cellular Research, National Cancer Centre, Singapore, Singapore
| | - Huai-Xiang Hao
- Oncology Drug Discovery Pharmacology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA
| | - Alan Huang
- Oncology Drug Discovery Pharmacology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA
| | - Youzhen Wang
- Oncology Drug Discovery Pharmacology, Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, MA, 02139, USA
| | - Diana Graus Porta
- Oncology Translational Research, Novartis Institutes for Biomedical Research at Basel, Basel, Switzerland
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14
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Liu PCC, Koblish H, Wu L, Bowman K, Diamond S, DiMatteo D, Zhang Y, Hansbury M, Rupar M, Wen X, Collier P, Feldman P, Klabe R, Burke KA, Soloviev M, Gardiner C, He X, Volgina A, Covington M, Ruggeri B, Wynn R, Burn TC, Scherle P, Yeleswaram S, Yao W, Huber R, Hollis G. INCB054828 (pemigatinib), a potent and selective inhibitor of fibroblast growth factor receptors 1, 2, and 3, displays activity against genetically defined tumor models. PLoS One 2020; 15:e0231877. [PMID: 32315352 PMCID: PMC7313537 DOI: 10.1371/journal.pone.0231877] [Citation(s) in RCA: 112] [Impact Index Per Article: 22.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2019] [Accepted: 04/02/2020] [Indexed: 01/11/2023] Open
Abstract
Alterations in fibroblast growth factor receptor (FGFR) genes have been
identified as potential driver oncogenes. Pharmacological targeting of FGFRs may
therefore provide therapeutic benefit to selected cancer patients, and
proof-of-concept has been established in early clinical trials of FGFR
inhibitors. Here, we present the molecular structure and preclinical
characterization of INCB054828 (pemigatinib), a novel, selective inhibitor of
FGFR 1, 2, and 3, currently in phase 2 clinical trials. INCB054828
pharmacokinetics and pharmacodynamics were investigated using cell lines and
tumor models, and the antitumor effect of oral INCB054828 was investigated using
xenograft tumor models with genetic alterations in FGFR1, 2, or 3. Enzymatic
assays with recombinant human FGFR kinases showed potent inhibition of FGFR1, 2,
and 3 by INCB054828 (half maximal inhibitory concentration [IC50]
0.4, 0.5, and 1.0 nM, respectively) with weaker activity against FGFR4
(IC50 30 nM). INCB054828 selectively inhibited growth of tumor
cell lines with activation of FGFR signaling compared with cell lines lacking
FGFR aberrations. The preclinical pharmacokinetic profile suggests target
inhibition is achievable by INCB054828 in vivo with low oral doses. INCB054828
suppressed the growth of xenografted tumor models with FGFR1, 2, or 3
alterations as monotherapy, and the combination of INCB054828 with cisplatin
provided significant benefit over either single agent, with an acceptable
tolerability. The preclinical data presented for INCB054828, together with
preliminary clinical observations, support continued investigation in patients
with FGFR alterations, such as fusions and activating mutations.
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MESH Headings
- Administration, Oral
- Animals
- Cell Line, Tumor
- Female
- Half-Life
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Nude
- Mice, SCID
- Morpholines/chemistry
- Morpholines/pharmacokinetics
- Morpholines/therapeutic use
- Neoplasms/drug therapy
- Neoplasms/pathology
- Protein Kinase Inhibitors/chemistry
- Protein Kinase Inhibitors/pharmacokinetics
- Protein Kinase Inhibitors/therapeutic use
- Pyrimidines/chemistry
- Pyrimidines/pharmacokinetics
- Pyrimidines/therapeutic use
- Pyrroles/chemistry
- Pyrroles/pharmacokinetics
- Pyrroles/therapeutic use
- Rats
- Rats, Nude
- Receptor, Fibroblast Growth Factor, Type 1/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 1/metabolism
- Receptor, Fibroblast Growth Factor, Type 2/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 2/metabolism
- Receptor, Fibroblast Growth Factor, Type 3/antagonists & inhibitors
- Receptor, Fibroblast Growth Factor, Type 3/metabolism
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Phillip C. C. Liu
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Holly Koblish
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
- * E-mail:
| | - Liangxing Wu
- Discovery Chemistry, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Kevin Bowman
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Sharon Diamond
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Darlise DiMatteo
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Yue Zhang
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Michael Hansbury
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Mark Rupar
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Xiaoming Wen
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Paul Collier
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Patricia Feldman
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Ronald Klabe
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Krista A. Burke
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Maxim Soloviev
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Christine Gardiner
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Xin He
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Alla Volgina
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Maryanne Covington
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Bruce Ruggeri
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Richard Wynn
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Timothy C. Burn
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Peggy Scherle
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Swamy Yeleswaram
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Wenqing Yao
- Discovery Chemistry, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Reid Huber
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
| | - Gregory Hollis
- Discovery Biology, Incyte Research Institute, Wilmington, Delaware,
United States of America
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15
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Sydor S, Best J, Messerschmidt I, Manka P, Vilchez-Vargas R, Brodesser S, Lucas C, Wegehaupt A, Wenning C, Aßmuth S, Hohenester S, Link A, Faber KN, Moshage H, Cubero FJ, Friedman SL, Gerken G, Trauner M, Canbay A, Bechmann LP. Altered Microbiota Diversity and Bile Acid Signaling in Cirrhotic and Noncirrhotic NASH-HCC. Clin Transl Gastroenterol 2020; 11:e00131. [PMID: 32352707 PMCID: PMC7145043 DOI: 10.14309/ctg.0000000000000131] [Citation(s) in RCA: 77] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/10/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVES The precipitous increase in nonalcoholic steatohepatitis (NASH) is accompanied by a dramatic increase in the incidence of NASH-related hepatocellular carcinoma (HCC). HCC in NASH has a higher propensity to arise without pre-existing cirrhosis compared with other chronic liver diseases. METHODS To identify the potential links between liver and gut in NASH-related hepatocarcinogenesis, we compared the gut microbiota and mediators of bile acid (BA) signaling in the absence or presence of cirrhosis through the analysis of stool and serum samples from patients with NASH non-HCC and NASH-HCC and healthy volunteers. RESULTS Serum levels of total and individual BA were higher in NASH compared with healthy controls. Furthermore, serum levels of the primary conjugated BAs glycine-conjugated cholic acid, taurine-conjugated cholic acid, glycine-conjugated chenodeoxycholic acid, and taurine-conjugated chenodeoxycholic acid were significantly increased in cirrhotic vs noncirrhotic patients, independent of the occurrence of HCC. By contrast, serum FGF19 levels were higher in patients with NASH-HCC and associated with tumor markers as well as an attenuation of BA synthesis. Specific alterations in the gut microbiome were found for several bacteria involved in the BA metabolism including Bacteroides and Lactobacilli. Specifically, the abundance of Lactobacilli was associated with progressive disease, serum BA levels, and liver injury in NASH and NASH-HCC. DISCUSSION Here, we demonstrate a clear association of the altered gut microbiota and primary conjugated BA composition in cirrhotic and noncirrhotic patients with NASH-HCC. Microbiota-associated alterations in BA homeostasis and farnesoid X receptor signaling, via FGF19, might thus contribute to fibrogenesis, liver injury, and tumorigenesis in NASH-HCC.
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Affiliation(s)
- Svenja Sydor
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
| | - Jan Best
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
| | - Insa Messerschmidt
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
| | - Paul Manka
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
| | - Ramiro Vilchez-Vargas
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
| | - Susanne Brodesser
- CECAD Research Center, CECAD Lipidomics Facility, University of Cologne, Cologne, Germany
| | - Christina Lucas
- CECAD Research Center, CECAD Lipidomics Facility, University of Cologne, Cologne, Germany
| | - Annemarie Wegehaupt
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
| | - Chiara Wenning
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
| | - Sophia Aßmuth
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
| | - Simon Hohenester
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany;
| | - Alexander Link
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
| | - Klaas Nico Faber
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Han Moshage
- Department of Gastroenterology and Hepatology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Francisco Javier Cubero
- Department of Immunology, Ophthalmology and ENT, Complutense University School of Medicine, Madrid, Spain
- 12 de Octubre Health Research Institute (imas 12), Madrid, Spain
| | - Scott L. Friedman
- Division of Liver Diseases, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
| | - Guido Gerken
- Department of Gastroenterology and Hepatology, University Hospital Essen, Essen, Germany;
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Ali Canbay
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
| | - Lars P. Bechmann
- Department of Gastroenterology, Hepatology, and Infectious Diseases, Otto von Guericke University Hospital Magdeburg, Magdeburg, Germany
- Department of Medicine, Ruhr University Bochum, University Hospital Knappschaftskrankenhaus Bochum, Bochum, Germany
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16
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FGFR1 and FGFR4 oncogenicity depends on n-cadherin and their co-expression may predict FGFR-targeted therapy efficacy. EBioMedicine 2020; 53:102683. [PMID: 32114392 PMCID: PMC7047190 DOI: 10.1016/j.ebiom.2020.102683] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2019] [Revised: 02/05/2020] [Accepted: 02/05/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Fibroblast growth factor receptor (FGFR)1 and FGFR4 have been associated with tumorigenesis in a variety of tumour types. As a therapeutic approach, their inhibition has been attempted in different types of malignancies, including lung cancer, and was initially focused on FGFR1-amplified tumours, though with limited success. METHODS In vitro and in vivo functional assessments of the oncogenic potential of downregulated/overexpressed genes in isogenic cell lines were performed, as well as inhibitor efficacy tests in vitro and in vivo in patient-derived xenografts (PDXs). mRNA was extracted from FFPE non-small cell lung cancer samples to determine the prognostic potential of the genes under study. FINDINGS We provide in vitro and in vivo evidence showing that expression of the adhesion molecule N-cadherin is key for the oncogenic role of FGFR1/4 in non-small cell lung cancer. According to this, assessment of the expression of genes in different lung cancer patient cohorts showed that FGFR1 or FGFR4 expression alone showed no prognostic potential, and that only co-expression of FGFR1 and/or FGFR4 with N-cadherin inferred a poorer outcome. Treatment of high-FGFR1 and/or FGFR4-expressing lung cancer cell lines and patient-derived xenografts with selective FGFR inhibitors showed high efficacy, but only in models with high FGFR1/4 and N-cadherin expression. INTERPRETATION Our data show that the determination of the expression of FGFR1 or FGFR4 alone is not sufficient to predict anti-FGFR therapy efficacy; complementary determination of N-cadherin expression may further optimise patient selection for this therapeutic strategy.
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17
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Lin X, Yosaatmadja Y, Kalyukina M, Middleditch MJ, Zhang Z, Lu X, Ding K, Patterson AV, Smaill JB, Squire CJ. Rotational Freedom, Steric Hindrance, and Protein Dynamics Explain BLU554 Selectivity for the Hinge Cysteine of FGFR4. ACS Med Chem Lett 2019; 10:1180-1186. [PMID: 31413803 DOI: 10.1021/acsmedchemlett.9b00196] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 07/03/2019] [Indexed: 12/16/2022] Open
Abstract
Aberration in FGFR4 signaling drives carcinogenesis and progression in a subset of hepatocellular carcinoma (HCC) patients, thereby making FGFR4 an attractive molecular target for this disease. Selective FGFR4 inhibition can be achieved through covalently targeting a poorly conserved cysteine residue in the FGFR4 kinase domain. We report mass spectrometry assays and cocrystal structures of FGFR4 in covalent complex with the clinical candidate BLU554 and with a series of four structurally related inhibitors that define the inherent reactivity and selectivity profile of these molecules. We further reveal the structure of FGFR1 with one of our inhibitors and show that off-target covalent binding can occur through an alternative conformation that supports targeting of a cysteine conserved in all members of the FGFR family. Collectively, we propose that rotational freedom, steric hindrance, and protein dynamics explain the exceptional selectivity profile of BLU554 for targeting FGFR4.
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Affiliation(s)
- Xiaojing Lin
- School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Yuliana Yosaatmadja
- School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Maria Kalyukina
- School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Martin J. Middleditch
- School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Zhen Zhang
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Xiaoyun Lu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Ke Ding
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Development of Chinese Ministry of Education (MOE), School of Pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou 510632, China
| | - Adam V. Patterson
- Auckland Cancer Society Research Centre, the University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, c/o The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Jeff B. Smaill
- Auckland Cancer Society Research Centre, the University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, c/o The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
| | - Christopher J. Squire
- School of Biological Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, c/o The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
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18
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Quintanal-Villalonga A, Ferrer I, Molina-Pinelo S, Paz-Ares L. A patent review of FGFR4 selective inhibition in cancer (2007-2018). Expert Opin Ther Pat 2019; 29:429-438. [DOI: 10.1080/13543776.2019.1624720] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Affiliation(s)
| | - Irene Ferrer
- CNIO-H12O Lung Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
| | - Sonia Molina-Pinelo
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
- Instituto de Biomedicina de Sevilla (IBIS) (HUVR, CSIC, Universidad de Sevilla), Sevilla, Spain
| | - Luis Paz-Ares
- CNIO-H12O Lung Clinical Cancer Research Unit, Fundación de Investigación Biomédica i+12 & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, Spain
- Medical Oncology Department, Hospital Universitario Doce de Octubre & Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
- Medical School, Universidad Complutense, Madrid, Spain
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Schadt HS, Wolf A, Mahl JA, Wuersch K, Couttet P, Schwald M, Fischer A, Lienard M, Emotte C, Teng CH, Skuba E, Richardson TA, Manenti L, Weiss A, Graus Porta D, Fairhurst RA, Kullak-Ublick GA, Chibout SD, Pognan F, Kluwe W, Kinyamu-Akunda J. Bile Acid Sequestration by Cholestyramine Mitigates FGFR4 Inhibition-Induced ALT Elevation. Toxicol Sci 2019; 163:265-278. [PMID: 29432567 DOI: 10.1093/toxsci/kfy031] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The FGF19- fibroblast growth factor receptor (FGFR4)-βKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma, establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for hepatocellular carcinoma, currently in phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one, increased BA pool size, decreased serum cholesterol and diarrhea in dogs. FGF401 was also associated with increases of serum aminotransferases, primarily alanine aminotransferase (ALT), in the absence of any observable adverse histopathological findings in the liver, or in any other organs. We hypothesized that the increase in ALT could be secondary to increased BAs and conducted an investigative study in dogs with FGF401 and coadministration of the BA sequestrant cholestyramine (CHO). CHO prevented and reversed FGF401-related increases in ALT in dogs in parallel to its ability to reduce BAs in the circulation. Correlation analysis showed that FGF401-mediated increases in ALT strongly correlated with increases in taurolithocholic acid and taurodeoxycholic acid, the major secondary BAs in dog plasma, indicating a mechanistic link between ALT elevation and changes in BA pool hydrophobicity. Thus, CHO may offer the potential to mitigate elevations in serum aminotransferases in human subjects that are caused by targeted FGFR4 inhibition and elevated intracellular BA levels.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Corinne Emotte
- PK Sciences, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland
| | - Chi-Hse Teng
- Biostatistics and Pharmacometrics, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts 02139
| | | | | | - Luigi Manenti
- Oncology, Novartis Institutes for Biomedical Research, East Hanover, New Jersey 07936
| | | | | | - Robin A Fairhurst
- Global Discovery Chemistry, Novartis Institutes for Biomedical Research, 4002 Basel, Switzerland
| | - Gerd A Kullak-Ublick
- Mechanistic Safety, Novartis Global Drug Development, 4002 Basel, Switzerland.,Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland
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20
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Quintanal-Villalonga A, Molina-Pinelo S, Cirauqui C, Ojeda-Márquez L, Marrugal Á, Suarez R, Conde E, Ponce-Aix S, Enguita AB, Carnero A, Ferrer I, Paz-Ares L. FGFR1 Cooperates with EGFR in Lung Cancer Oncogenesis, and Their Combined Inhibition Shows Improved Efficacy. J Thorac Oncol 2019; 14:641-655. [PMID: 30639621 DOI: 10.1016/j.jtho.2018.12.021] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2018] [Revised: 11/23/2018] [Accepted: 12/04/2018] [Indexed: 01/13/2023]
Abstract
INTRODUCTION There is substantial evidence for the oncogenic effects of fibroblast growth factor receptor 1 (FGFR1) in many types of cancer, including lung cancer, but the role of this receptor has not been addressed specifically in lung adenocarcinoma. METHODS We performed FGFR1 and EGFR overexpression and co-overexpression assays in adenocarcinoma and in inmortalized lung cell lines, and we also carried out surrogate and interaction assays. We performed monotherapy and combination EGFR/FGFR inhibitor sensitivity assays in vitro and in vivo in cell line- and patient-derived xenografts. We determined FGFR1 mRNA expression in a cohort of patients with anti-EGFR therapy-treated adenocarcinoma. RESULTS We have reported a cooperative interaction between FGFR1 and EGFR in this context, resulting in increased EGFR activation and oncogenic signaling. We have provided in vitro and in vivo evidence indicating that FGFR1 expression increases tumorigenicity in cells with high EGFR activation in EGFR-mutated and EGFR wild-type models. At the clinical level, we have shown that high FGFR1 expression levels predict higher resistance to erlotinib or gefitinib in a cohort of patients with tyrosine kinase inhibitor-treated EGFR-mutated and EGFR wild-type lung adenocarcinoma. Dual EGFR and FGFR inhibition in FGFR1-overexpressing, EGFR-activated models shows synergistic effects on tumor growth in vitro and in cell line- and patient-derived xenografts, suggesting that patients with tumors bearing these characteristics may benefit from combined EGFR/FGFR inhibition. CONCLUSION These results support the extended the use of EGFR inhibitors beyond monotherapy in the EGFR-mutated adenocarcinoma setting in combination with FGFR inhibitors for selected patients with increased FGFR1 overexpression and EGFR activation.
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Affiliation(s)
- Alvaro Quintanal-Villalonga
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; Program in Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Sonia Molina-Pinelo
- Insitute for Biomedical Research in Seville (UHVR, SNRC, Seville University), Seville, Spain; CIBERONC, Madrid, Spain
| | - Cristina Cirauqui
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Laura Ojeda-Márquez
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain
| | - Ángela Marrugal
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Rocío Suarez
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain
| | - Esther Conde
- CIBERONC, Madrid, Spain; Therapeutic Targets Laboratory, University Hospital HM Sanchinarro, Madrid, Spain
| | - Santiago Ponce-Aix
- CIBERONC, Madrid, Spain; Medical Oncology Department, University Hospital Doce de Octubre Madrid, Spain
| | - Ana Belén Enguita
- Pathological Anatomy Department, University Hospital Doce de Octubre, Madrid, Spain
| | - Amancio Carnero
- Insitute for Biomedical Research in Seville (UHVR, SNRC, Seville University), Seville, Spain; CIBERONC, Madrid, Spain
| | - Irene Ferrer
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain.
| | - Luis Paz-Ares
- H12O-CNIO Lung Cancer Clinical Research Unit, Biomedical Research Foundation i+12, Madrid, Spain; H12O-CNIO Lung Cancer Clinical Research Unit, Spanish National Cancer Research Centre (CNIO), Madrid, Spain; CIBERONC, Madrid, Spain; Medical Oncology Department, University Hospital Doce de Octubre Madrid, Spain; Medical School, Complutense University, Madrid, Spain
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21
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Donkers JM, Roscam Abbing RLP, van de Graaf SFJ. Developments in bile salt based therapies: A critical overview. Biochem Pharmacol 2018; 161:1-13. [PMID: 30582898 DOI: 10.1016/j.bcp.2018.12.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 12/20/2018] [Indexed: 01/06/2023]
Abstract
Bile acids, amphipathic molecules known for their facilitating role in fat absorption, are also recognized as signalling molecules acting via nuclear and membrane receptors. Of the bile acid-activated receptors, the Farnesoid X Receptor (FXR) and the G protein-coupled bile acid receptor-1 (Gpbar1 or TGR5) have been studied most extensively. Bile acid signaling is critical in the regulation of bile acid metabolism itself, but it also plays a significant role in glucose, lipid and energy metabolism. Activation of FXR and TGR5 leads to reduced hepatic bile salt load, improved insulin sensitivity and glucose regulation, increased energy expenditure, and anti-inflammatory effects. These beneficial effects render bile acid signaling an interesting therapeutic target for the treatment of diseases such as cholestasis, non-alcoholic fatty liver disease, and diabetes. Here, we summarize recent findings on bile acid signaling and discuss potential and current limitations of bile acid receptor agonist and modulators of bile acid transport as future therapeutics for a wide-spectrum of diseases.
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Affiliation(s)
- Joanne M Donkers
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands
| | - Reinout L P Roscam Abbing
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands
| | - Stan F J van de Graaf
- Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands; Amsterdam UMC, University of Amsterdam, Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology and Metabolism, Amsterdam, the Netherlands.
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22
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Somm E, Jornayvaz FR. Fibroblast Growth Factor 15/19: From Basic Functions to Therapeutic Perspectives. Endocr Rev 2018; 39:960-989. [PMID: 30124818 DOI: 10.1210/er.2018-00134] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2018] [Accepted: 07/10/2018] [Indexed: 12/11/2022]
Abstract
Discovered 20 years ago, fibroblast growth factor (FGF)19, and its mouse ortholog FGF15, were the first members of a new subfamily of FGFs able to act as hormones. During fetal life, FGF15/19 is involved in organogenesis, affecting the development of the ear, eye, heart, and brain. At adulthood, FGF15/19 is mainly produced by the ileum, acting on the liver to repress hepatic bile acid synthesis and promote postprandial nutrient partitioning. In rodents, pharmacologic doses of FGF19 induce the same antiobesity and antidiabetic actions as FGF21, with these metabolic effects being partly mediated by the brain. However, activation of hepatocyte proliferation by FGF19 has long been a challenge to its therapeutic use. Recently, genetic reengineering of the molecule has resolved this issue. Despite a global overlap in expression pattern and function, murine FGF15 and human FGF19 exhibit several differences in terms of regulation, molecular structure, signaling, and biological properties. As most of the knowledge originates from the use of FGF19 in murine models, differences between mice and humans in the biology of FGF15/19 have to be considered for a successful translation from bench to bedside. This review summarizes the basic knowledge concerning FGF15/19 in mice and humans, with a special focus on regulation of production, morphogenic properties, hepatocyte growth, bile acid homeostasis, as well as actions on glucose, lipid, and energy homeostasis. Moreover, implications and therapeutic perspectives concerning FGF19 in human diseases (including obesity, type 2 diabetes, hepatic steatosis, biliary disorders, and cancer) are also discussed.
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Affiliation(s)
- Emmanuel Somm
- Service of Endocrinology, Diabetes, Hypertension, and Nutrition, Geneva University Hospitals, University of Geneva Medical School, Geneva, Switzerland
| | - François R Jornayvaz
- Service of Endocrinology, Diabetes, Hypertension, and Nutrition, Geneva University Hospitals, University of Geneva Medical School, Geneva, Switzerland
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23
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Abstract
Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.
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Affiliation(s)
- Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, USA
| | - Guoxiang Xie
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, USA
| | - Weiping Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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Trichlorobenzene-substituted azaaryl compounds as novel FGFR inhibitors exhibiting potent antitumor activity in bladder cancer cells in vitro and in vivo. Oncotarget 2018; 7:26374-87. [PMID: 27029060 PMCID: PMC5041986 DOI: 10.18632/oncotarget.8380] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 03/14/2016] [Indexed: 01/16/2023] Open
Abstract
In the present study, we examined the antitumor activity of a series of trichlorobenzene-substituted azaaryl compounds and identified MPT0L145 as a novel FGFR inhibitor with better selectivity for FGFR1, 2 and 3. It was preferentially effective in FGFR-activated cancer cells, including bladder cancer cell lines expressing FGFR3-TACC3 fusion proteins (RT-112, RT-4). MPT0L145 decreased the phosphorylation of FGFR1, FGFR3 and their downstream proteins (FRS2, ERK and Akt). Mechanistically, cDNA microarray analysis revealed that MPT0L145 decreased genes associated cell cycle progression, and increased genes associated with autophagy pathway. Accordingly, the data revealed that MPT0L145 induced G0/G1 cell cycle arrest and decreased protein levels of cyclin E. Moreover, we provided the evidence that autophagy contributes to FGFR inhibitor-related cell death. Finally, MPT0L145 exhibited comparable antitumor activity to cisplatin with better safety in a RT-112 xenograft model. Taken together, these findings support the utility of MPT0L145 as a novel FGFR inhibitor, providing a strong rationale for further evaluation of this compound as a therapeutic agent for bladder cancers.
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25
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Joshi JJ, Coffey H, Corcoran E, Tsai J, Huang CL, Ichikawa K, Prajapati S, Hao MH, Bailey S, Wu J, Rimkunas V, Karr C, Subramanian V, Kumar P, MacKenzie C, Hurley R, Satoh T, Yu K, Park E, Rioux N, Kim A, Lai WG, Yu L, Zhu P, Buonamici S, Larsen N, Fekkes P, Wang J, Warmuth M, Reynolds DJ, Smith PG, Selvaraj A. H3B-6527 Is a Potent and Selective Inhibitor of FGFR4 in FGF19-Driven Hepatocellular Carcinoma. Cancer Res 2018; 77:6999-7013. [PMID: 29247039 DOI: 10.1158/0008-5472.can-17-1865] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Revised: 08/23/2017] [Accepted: 10/10/2017] [Indexed: 01/18/2023]
Abstract
Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response. Moreover, coadministration of the CDK4/6 inhibitor palbociclib in combination with H3B-6527 could effectively trigger tumor regression in a xenograft model of HCC. Overall, our results offer preclinical proof of concept for H3B-6527 as a candidate therapeutic agent for HCC cases that exhibit increased expression of FGF19. Cancer Res; 77(24); 6999-7013. ©2017 AACR.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Jeremy Wu
- H3 Biomedicine, Cambridge, Massachusetts
| | | | - Craig Karr
- H3 Biomedicine, Cambridge, Massachusetts
| | | | | | | | | | | | - Kun Yu
- H3 Biomedicine, Cambridge, Massachusetts
| | | | | | - Amy Kim
- H3 Biomedicine, Cambridge, Massachusetts
| | | | - Lihua Yu
- H3 Biomedicine, Cambridge, Massachusetts
| | - Ping Zhu
- H3 Biomedicine, Cambridge, Massachusetts
| | | | | | | | - John Wang
- H3 Biomedicine, Cambridge, Massachusetts
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Brennan FR, Cavagnaro J, McKeever K, Ryan PC, Schutten MM, Vahle J, Weinbauer GF, Marrer-Berger E, Black LE. Safety testing of monoclonal antibodies in non-human primates: Case studies highlighting their impact on human risk assessment. MAbs 2018; 10:1-17. [PMID: 28991509 PMCID: PMC5800363 DOI: 10.1080/19420862.2017.1389364] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 10/01/2017] [Accepted: 10/03/2017] [Indexed: 12/16/2022] Open
Abstract
Monoclonal antibodies (mAbs) are improving the quality of life for patients suffering from serious diseases due to their high specificity for their target and low potential for off-target toxicity. The toxicity of mAbs is primarily driven by their pharmacological activity, and therefore safety testing of these drugs prior to clinical testing is performed in species in which the mAb binds and engages the target to a similar extent to that anticipated in humans. For highly human-specific mAbs, this testing often requires the use of non-human primates (NHPs) as relevant species. It has been argued that the value of these NHP studies is limited because most of the adverse events can be predicted from the knowledge of the target, data from transgenic rodents or target-deficient humans, and other sources. However, many of the mAbs currently in development target novel pathways and may comprise novel scaffolds with multi-functional domains; hence, the pharmacological effects and potential safety risks are less predictable. Here, we present a total of 18 case studies, including some of these novel mAbs, with the aim of interrogating the value of NHP safety studies in human risk assessment. These studies have identified mAb candidate molecules and pharmacological pathways with severe safety risks, leading to candidate or target program termination, as well as highlighting that some pathways with theoretical safety concerns are amenable to safe modulation by mAbs. NHP studies have also informed the rational design of safer drug candidates suitable for human testing and informed human clinical trial design (route, dose and regimen, patient inclusion and exclusion criteria and safety monitoring), further protecting the safety of clinical trial participants.
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Affiliation(s)
- Frank R. Brennan
- Non-Clinical Safety, UCB, Slough, Berkshire, United Kingdom, SL1 3WE
| | | | - Kathleen McKeever
- Ultragenyx Pharmaceuticals, 60 Leveroni Court, Novato, California, United States
| | - Patricia C. Ryan
- Toxicology, Medimmune LLC, One Medimmune Way, Gaithersburg, Maryland, United States
| | - Melissa M. Schutten
- Department of Toxicology, Genetech, 1 DNA Way, San Francisco, California, United States
| | - John Vahle
- Toxicology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, United States
| | | | - Estelle Marrer-Berger
- Novartis Pharma, Preclinical Safety, F Hoffmann-La Roche Ltd., Grenzacherstrasse 124, Basel, Basel-Stadt, Switzerland CH-4070
| | - Lauren E. Black
- Safety Assessment, Charles River Laboratories, 6995 Longley Lane, Reno, Nevada, United States
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27
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Zhang X, Kong M, Zhang Z, Xu S, Yan F, Wei L, Zhou J. FGF19 genetic amplification as a potential therapeutic target in lung squamous cell carcinomas. Thorac Cancer 2017; 8:655-665. [PMID: 28906590 PMCID: PMC5668513 DOI: 10.1111/1759-7714.12504] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2017] [Revised: 08/08/2017] [Accepted: 08/09/2017] [Indexed: 11/29/2022] Open
Abstract
Background Although FGF19 gene aberrations are associated with carcinogenesis and progression in human cancers, the roles of FGF19 genetic amplification and expression in Chinese patients with lung squamous cell carcinoma (LSCC) and FGF19 amplification as a potential therapeutic target for LSCC are not well understood. Methods Fluorescence in situ hybridization analysis and quantitative real‐time‐PCR was used to detect FGF19 genetic amplification and FGF19 messenger RNA expression in LSCC tumor and paired adjacent samples. Small interfering RNA and short hairpin RNA were used to knockdown FGF19 in vitro and in vivo. Results FGF19 amplification was identified in a subset of LSCC patients (37.5%, 15/40), and upregulation of FGF19 expression was found in 60% (24/40) of tumor tissues compared to adjacent non‐tumorous tissues. Correlation analysis with clinicopathologic parameters showed that FGF19 upregulation was significantly associated with heavy smoking. Small interfering RNA knockdown of FGF19 led to the significant inhibition of cell growth and induced apoptosis in LSCC cells carrying the amplified FGF19 gene, but these effects was not observed in non‐amplified LSCC cells. Interfering FGF19 expression with short hairpin RNA also resulted in tumor growth inhibition and induced apoptosis in LSCC xenografts with amplified FGF19 in tumor cells. Conclusion Our results suggested that FGF19 signaling activation is required for cell growth and survival of FGF19 amplified LSCC cells, both in vitro and in vivo. Intervention of FGF19 activation could be a potential therapeutic strategy for LSCC patients with FGF19 amplification.
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Affiliation(s)
- Xiaochen Zhang
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Mei Kong
- Department of Pathology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Zhen Zhang
- Department of Oncology, Hangzhou Cancer Hospital, Hangzhou, China
| | - Suzhen Xu
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Feifei Yan
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Liyuan Wei
- Department of Medical Oncology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
| | - Jianying Zhou
- Department of Respiratory Disease, Thoracic Disease Centre, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
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28
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Bouattour M, Raymond E, Faivre S. Carcinome hépatocellulaire : nouveaux concepts, nouvelles molécules et nouvelles approches. ONCOLOGIE 2017; 19:168-176. [DOI: 10.1007/s10269-017-2712-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Trauner M, Fuchs CD, Halilbasic E, Paumgartner G. New therapeutic concepts in bile acid transport and signaling for management of cholestasis. Hepatology 2017; 65:1393-1404. [PMID: 27997980 DOI: 10.1002/hep.28991] [Citation(s) in RCA: 169] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2016] [Revised: 12/05/2016] [Accepted: 12/05/2016] [Indexed: 12/13/2022]
Abstract
The identification of the key regulators of bile acid (BA) synthesis and transport within the enterohepatic circulation has revealed potential targets for pharmacological therapies of cholestatic liver diseases. Novel drug targets include the bile BA receptors, farnesoid X receptor and TGR5, the BA-induced gut hormones, fibroblast growth factor 19 and glucagon-like peptide 1, and the BA transport systems, apical sodium-dependent bile acid transporter and Na+ -taurocholate cotransporting polypeptide, within the enterohepatic circulation. Moreover, BA derivatives undergoing cholehepatic shunting may allow improved targeting to the bile ducts. This review focuses on the pathophysiological basis, mechanisms of action, and clinical development of novel pharmacological strategies targeting BA transport and signaling in cholestatic liver diseases. (Hepatology 2017;65:1393-1404).
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Affiliation(s)
- Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Claudia Daniela Fuchs
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Emina Halilbasic
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
| | - Gustav Paumgartner
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria
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Chae YK, Ranganath K, Hammerman PS, Vaklavas C, Mohindra N, Kalyan A, Matsangou M, Costa R, Carneiro B, Villaflor VM, Cristofanilli M, Giles FJ. Inhibition of the fibroblast growth factor receptor (FGFR) pathway: the current landscape and barriers to clinical application. Oncotarget 2017; 8:16052-16074. [PMID: 28030802 PMCID: PMC5362545 DOI: 10.18632/oncotarget.14109] [Citation(s) in RCA: 239] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 11/22/2016] [Indexed: 12/19/2022] Open
Abstract
The fibroblast growth factor/fibroblast growth factor receptor (FGF/FGFR) is a tyrosine kinase signaling pathway that has a fundamental role in many biologic processes including embryonic development, tissue regeneration, and angiogenesis. Increasing evidence indicates that this pathway plays a critical role in oncogenesis via gene amplification, activating mutations, or translocation in tumors of various histologies. With multiplex sequencing technology, the detection of FGFR aberrations has become more common and is tied to cancer cell proliferation, resistance to anticancer therapies, and neoangiogenesis. Inhibition of FGFR signaling appears promising in preclinical studies, suggesting a pathway of clinical interest in the development of targeted therapy. Phase I trials have demonstrated a manageable toxicity profile. Currently, there are multiple FGFR inhibitors under study with many non-selective (multi-kinase) inhibitors demonstrating limited clinical responses. As we progress from the first generation of non-selective drugs to the second generation of selective FGFR inhibitors, it is clear that FGFR aberrations do not behave uniformly across cancer types; thus, a deeper understanding of biomarker strategies is undoubtedly warranted. This review aims to consolidate data from recent clinical trials with a focus on selective FGFR inhibitors. As Phase II clinical trials emerge, concentration on patient selection as it pertains to predicting response to therapy, feasible methods for overcoming toxicity, and the likelihood of combination therapies should be utilized. We will also discuss qualities that may be desirable in future generations of FGFR inhibitors, with the hope that overcoming these current barriers will expedite the availability of this novel class of medications.
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Affiliation(s)
- Young Kwang Chae
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Keerthi Ranganath
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | | | - Christos Vaklavas
- Division of Hematology Oncology, University of Alabama Birmingham, Birmingham, AL, USA
| | - Nisha Mohindra
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Aparna Kalyan
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Maria Matsangou
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ricardo Costa
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
| | - Benedito Carneiro
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Victoria M. Villaflor
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Massimo Cristofanilli
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Francis J. Giles
- Developmental Therapeutics Program of the Division of Hematology Oncology, Chicago, IL, USA
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA
- Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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31
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Tan Q, Li F, Wang G, Xia W, Li Z, Niu X, Ji W, Yuan H, Xu Q, Luo Q, Zhang J, Lu S. Identification of FGF19 as a prognostic marker and potential driver gene of lung squamous cell carcinomas in Chinese smoking patients. Oncotarget 2017; 7:18394-402. [PMID: 26943773 PMCID: PMC4951296 DOI: 10.18632/oncotarget.7817] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2015] [Accepted: 01/24/2016] [Indexed: 11/25/2022] Open
Abstract
Comprehensive genomic characterizations of lung squamous cell carcinoma (LSCC) have been performed, but the differences between smokers (S-LSCC) and never smokers (NS-LSCC) are not clear, as NS-LSCC could be considered as a different disease from S-LSCC. In this study we delineated genomic alterations in a cohort of 21 NS-LSCC and 16 S-LSCC patients, and identified common gene mutations and amplifications as previously reported. Inclusion of more NS-LSCC patients enabled us to identify unreported S-LSCC- or NS-LSCC-specific alterations. Importantly, an amplification region containing FGF19, FGF3, FGF4 and CCND1 was found five-times more frequent in S-LSCC than in NS-LSCC. Amplification of FGF19 was validated in independent LSCC samples. Furthermore, FGF19 stimulated LSCC cell growth in vitro. These data implicate FGF19 as a potential driver gene in LSCC with clinic characteristics as smoking.
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Affiliation(s)
- Qiang Tan
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
| | - Fan Li
- State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Guan Wang
- Genomics Center, WuXi AppTec Co., Ltd., Shanghai 200131, China
| | - Weiliang Xia
- State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Ziming Li
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
| | - Xiaomin Niu
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
| | - Wenxiang Ji
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China.,State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Hong Yuan
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China.,State Key Laboratory of Oncogenes and Related Genes, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200030, China
| | - Qiang Xu
- Jiahui International Hospital, Shanghai 200120, China
| | - Qingquan Luo
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
| | - Jie Zhang
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
| | - Shun Lu
- Shanghai Lung Cancer Center, Lung Cancer Research Laboratory, Shanghai Chest Hospital Affiliated to Shanghai Jiao Tong University, Shanghai 200030, China
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32
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Wan ZY, Tian JS, Tan HWS, Chow AL, Sim AYL, Ban KHK, Long YC. Mechanistic target of rapamycin complex 1 is an essential mediator of metabolic and mitogenic effects of fibroblast growth factor 19 in hepatoma cells. Hepatology 2016; 64:1289-301. [PMID: 27178107 DOI: 10.1002/hep.28639] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 04/27/2016] [Indexed: 12/24/2022]
Abstract
UNLABELLED Fibroblast growth factor 19 (FGF19) is an important postprandial enterokine which regulates liver metabolism and hepatocyte proliferation. However, the precise mechanism by which FGF19 regulates these cellular effects is poorly understood. Given that mechanistic target of rapamycin complex 1 (mTORC1) regulates numerous postprandial adaptations, we investigated the potential role of mTORC1 in FGF19 action. We found that FGF19 activated mTORC1 in HepG2 and HuH7 human hepatoma cells, differentiated 3T3-L1 adipocytes and mouse liver. FGF19 activates the mTORC1-p70S6K and extracellular signal-regulated kinase (Erk)-p90RSK pathways independently to regulate S6 in an additive manner in hepatoma cells, but it uses mTORC1 as the primary pathway to regulate S6 in 3T3-L1 adipocytes. Thus, mTORC1 is a novel mediator of FGF19 signaling, which can act in parallel with Erk or function as the primary pathway to regulate S6. The FGF19-induced mTORC1 pathway requires amino acids for efficient signaling; thus, involvement of mTORC1 confers amino acid sensitivity to FGF19 signaling. Although Akt and Erk are known to activate mTORC1, we found that FGF19 signals to mTORC1 through a third recently identified mTORC1 regulator, Ras-like (Ral) protein. Pharmacological or genetic inhibition of RalA or RalB abolished FGF19-induced mTORC1 activation, demonstrating that Ral proteins are required for FGF19 to activate mTORC1. FGF19 induced metabolic gene expression, fatty acid oxidation, cell growth, and proliferation in HepG2 cells; and these effects were abolished by mTORC1 inhibition, demonstrating an essential role of mTORC1 in FGF19 action. CONCLUSION mTORC1 is a novel and essential mediator of FGF19 action on metabolic and mitogenic programs; thus, the involvement of mTORC1 in FGF19 signaling is an important factor to consider when targeting the pathway for cancer or diabetes therapy. (Hepatology 2016;64:1289-1301).
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Affiliation(s)
- Zhi Yi Wan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Johann Shane Tian
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Hayden Weng Siong Tan
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ai Lee Chow
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Arthur Yi Loong Sim
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Kenneth Hon Kim Ban
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.,Institute of Molecular and Cell Biology, A*STAR, Singapore
| | - Yun Chau Long
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
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Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 2016; 90:985-996. [PMID: 27457912 DOI: 10.1016/j.kint.2016.05.019] [Citation(s) in RCA: 279] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 04/26/2016] [Accepted: 05/19/2016] [Indexed: 12/14/2022]
Abstract
Patients with chronic kidney disease (CKD) develop increased levels of the phosphate-regulating hormone, fibroblast growth factor (FGF) 23, that are associated with a higher risk of mortality. Increases in inflammatory markers are another common feature that predicts poor clinical outcomes. Elevated FGF23 is associated with higher circulating levels of inflammatory cytokines in CKD, which can stimulate osteocyte production of FGF23. Here, we studied whether FGF23 can directly stimulate hepatic production of inflammatory cytokines in the absence of α-klotho, an FGF23 coreceptor in the kidney that is not expressed by hepatocytes. By activating FGF receptor isoform 4 (FGFR4), FGF23 stimulated calcineurin signaling in cultured hepatocytes, which increased the expression and secretion of inflammatory cytokines, including C-reactive protein. Elevating serum FGF23 levels increased hepatic and circulating levels of C-reactive protein in wild-type mice, but not in FGFR4 knockout mice. Administration of an isoform-specific FGFR4 blocking antibody reduced hepatic and circulating levels of C-reactive protein in the 5/6 nephrectomy rat model of CKD. Thus, FGF23 can directly stimulate hepatic secretion of inflammatory cytokines. Our findings indicate a novel mechanism of chronic inflammation in patients with CKD and suggest that FGFR4 blockade might have therapeutic anti-inflammatory effects in CKD.
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Zhao H, Lv F, Liang G, Huang X, Wu G, Zhang W, Yu L, Shi L, Teng Y. FGF19 promotes epithelial-mesenchymal transition in hepatocellular carcinoma cells by modulating the GSK3β/β- catenin signaling cascade via FGFR4 activation. Oncotarget 2016; 7:13575-13586. [PMID: 26498355 PMCID: PMC4924662 DOI: 10.18632/oncotarget.6185] [Citation(s) in RCA: 82] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Accepted: 10/04/2015] [Indexed: 12/12/2022] Open
Abstract
Compelling evidence suggests that the epithelial-mesenchymal transition (EMT) correlates with aggressiveness of tumors and poor survival. FGF19 has been shown to be involved in EMT in cholangiocarcinoma and colorectal cancer, however, molecular mechanisms underlying FGF19-induced EMT process in hepatocellular carcinoma (HCC) remain largely unknown. Here, we show the expression of FGF19 is significantly elevated and negatively associated with the expression of E-cadherin in HCC tissues and cell lines. Ectopic FGF19 expression promotes EMT and invasion in epithelial-like HCC cells through repression of E-cadherin expression, whereas FGF19 knockdown enhances E-cadherin expression and hence diminishes EMT traits in mesenchymal-like HCC cells, suggesting FGF19 exerts its tumor progressing functions as an EMT inducer. Interestingly, depletion of FGF19 cannot abrogate EMT traits in the presence of GSK3β inhibitors. Furthermore, FGF19-induced EMT can be markedly attenuated when FGFR4 is knocked out. These observations clearly indicate that FGFR4/GSK3β/β-catenin axis may play a pivotal role in FGF19-induced EMT in HCC cells. As FGF19 and its specific receptor FGFR4 are frequently amplified in HCC cells, selective targeting this signaling node may lend insights into a potential effective therapeutic approach for blocking metastasis of HCC.
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MESH Headings
- Apoptosis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Case-Control Studies
- Cell Movement
- Cell Proliferation
- Epithelial-Mesenchymal Transition
- Fibroblast Growth Factors/genetics
- Fibroblast Growth Factors/metabolism
- Glycogen Synthase Kinase 3 beta/genetics
- Glycogen Synthase Kinase 3 beta/metabolism
- Humans
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Prognosis
- Receptor, Fibroblast Growth Factor, Type 4/genetics
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Signal Transduction
- Tumor Cells, Cultured
- beta Catenin/genetics
- beta Catenin/metabolism
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Affiliation(s)
- Huakan Zhao
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Fenglin Lv
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Guizhao Liang
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Xiaobin Huang
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Gang Wu
- Third Affiliated Hospital, Third Military Medical University, Chongqing, PR China
| | - Wenfa Zhang
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Le Yu
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Lei Shi
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
| | - Yong Teng
- School of Life Sciences and School of Bioengineering, Chongqing University, Chongqing, PR China
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Repana D, Ross P. Targeting FGF19/FGFR4 Pathway: A Novel Therapeutic Strategy for Hepatocellular Carcinoma. Diseases 2015; 3:294-305. [PMID: 28943626 PMCID: PMC5548263 DOI: 10.3390/diseases3040294] [Citation(s) in RCA: 60] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2015] [Revised: 09/28/2015] [Accepted: 10/20/2015] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a lethal cancer with limited systemic therapeutic options. Liver carcinogenesis is a complex procedure and various pathways have been found to be deregulated which are potential targets for novel treatments. Aberrant signalling through FGF19 and its receptor FGFR4 seems to be the oncogenic driver for a subset of HCCs and is associated with poor prognosis. Inhibition of the pathway in preclinical models has shown antitumour activity and has triggered further evaluation of this strategy to in vivo models. This review aims to describe the role of the FGF19/FGFR4 pathway in hepatocellular carcinoma and its role as a potential predictive biomarker for novel targeted agents against FGF19/FGFR4 signalling.
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Affiliation(s)
- Dimitra Repana
- Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, SE1 9RT London, UK.
| | - Paul Ross
- Department of Medical Oncology, Guy's and St. Thomas' NHS Foundation Trust, SE1 9RT London, UK.
- Department of Oncology, King's College Hospital, SE19 1RT London, UK.
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36
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Zhang X, Wang Z, Tian L, Xie J, Zou G, Jiang F. Increased Expression of FGF19 Contributes to Tumor Progression and Cell Motility of Human Thyroid Cancer. Otolaryngol Head Neck Surg 2015; 154:52-8. [PMID: 26450751 DOI: 10.1177/0194599815609534] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/11/2015] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Numerous reports indicate a role for aberrant expression of fibroblast growth factor 19 (FGF19) in tumor development and progression, and several drugs have been developed to target it. The aim of this study was to investigate the clinical significance of FGF19 and examine whether it plays any roles in progression of thyroid cancer. STUDY DESIGN Translation research. SETTING Navy General Hospital of Chinese PLA, China. SUBJECTS AND METHODS Expression patterns of FGF19 protein in 100 paired formalin-fixed and paraffin-embedded cancerous and adjacent noncancerous tissues from patients with thyroid cancer were detected by immunohistochemistry. Then, in vitro migration and invasion assays of siRNA-targeted FGF19-transfected cells were performed. RESULTS Positive immunostaining of FGF19 protein expression was localized in cytoplasm with or without membrane of malignant cells and was observed in 82 (82.0%) of 100 patients with thyroid cancer. Statistically, the expression level of FGF19 protein in thyroid cancer tissues was significantly higher than that in normal tissues. In addition, FGF19 overexpression was significantly associated with the advanced tumor node metastasis staging (P = .008), the presence of extrathyroidal invasion (P = .01), lymph nodes metastasis (P = .01), and distant metastasis (P = .02). Furthermore, knockdown of FGF19 by transfection of siRNA-FGF19 could efficiently suppress the migration and invasion abilities of thyroid cancer cells in vitro. CONCLUSION Our data revealed that the increased expression of FGF19 might be involved in the malignant behaviors of thyroid cancer, highlighting its potential as a molecular marker for early diagnosis and as a possible target for therapeutic intervention of this disease.
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Affiliation(s)
- Xiliang Zhang
- Department of General Surgery, Navy General Hospital of Chinese PLA, Beijing, China
| | - Zhonghua Wang
- Department of General Surgery, Navy General Hospital of Chinese PLA, Beijing, China
| | - Lei Tian
- Department of General Surgery, Navy General Hospital of Chinese PLA, Beijing, China
| | - Jiangping Xie
- Department of General Surgery, Navy General Hospital of Chinese PLA, Beijing, China
| | - Guijun Zou
- Department of General Surgery, Navy General Hospital of Chinese PLA, Beijing, China
| | - Futing Jiang
- Department of General Surgery, Navy General Hospital of Chinese PLA, Beijing, China
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Padrissa-Altés S, Bachofner M, Bogorad RL, Pohlmeier L, Rossolini T, Böhm F, Liebisch G, Hellerbrand C, Koteliansky V, Speicher T, Werner S. Control of hepatocyte proliferation and survival by Fgf receptors is essential for liver regeneration in mice. Gut 2015; 64:1444-53. [PMID: 25416068 DOI: 10.1136/gutjnl-2014-307874] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
OBJECTIVE Fibroblast growth factors (Fgfs) are key orchestrators of development, and a role of Fgfs in tissue repair is emerging. Here we studied the consequences of inducible loss of Fgf receptor (Fgfr) 4, the major Fgf receptor (Fgfr) on hepatocytes, alone or in combination with Fgfr1 and Fgfr2, for liver regeneration after PH. DESIGN We used siRNA delivered via nanoparticles combined with liver-specific gene knockout to study Fgfr function in liver regeneration. Liver or blood samples were analysed using histology, immunohistochemistry,real-time RT-PCR, western blotting and ELISA. RESULTS siRNA-mediated knockdown of Fgfr4 severely affected liver regeneration due to impairment of hepatocyte proliferation combined with liver necrosis.Mechanistically, the proliferation defect resulted from inhibition of an Fgf15-Fgfr4-Stat3 signalling pathway,which is required for injury-induced expression of the Foxm1 transcription factor and subsequent cell cycle progression, while elevated levels of intrahepatic toxicbile acids were identified as the likely cause of the necrotic damage. Failure of liver mass restoration in Fgfr4 knockdown mice was prevented at least in part by compensatory hypertrophy of hepatocytes. Most importantly, our data revealed partially redundant functions of Fgf receptors in the liver, since knock down of Fgfr4 in mice lacking Fgfr1 and Fgfr2 in hepatocytes caused liver failure after PH due to severe liver necrosis and a defect in regeneration. CONCLUSIONS These results demonstrate that Fgfr signalling in hepatocytes is essential for liver regeneration and suggest activation of Fgfr signalling asa promising approach for the improvement of the liver's regenerative capacity.
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MESH Headings
- Animals
- Blotting, Western
- Cell Proliferation
- Cell Survival
- Cells, Cultured
- Cytokines/metabolism
- Disease Models, Animal
- Enzyme-Linked Immunosorbent Assay
- Hepatectomy/methods
- Hepatocytes/metabolism
- Hepatocytes/physiology
- Immunohistochemistry
- Liver/pathology
- Liver Regeneration/physiology
- Male
- Mice
- Mice, Knockout
- RNA, Small Interfering/analysis
- Real-Time Polymerase Chain Reaction/methods
- Receptor, Fibroblast Growth Factor, Type 4/genetics
- Receptor, Fibroblast Growth Factor, Type 4/metabolism
- Signal Transduction
- Statistics, Nonparametric
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Chan SL, Chan AWH, Yeo W. Novel therapeutic targets and predictive markers for hepatocellular carcinoma. Expert Opin Ther Targets 2015; 19:973-983. [PMID: 25910512 DOI: 10.1517/14728222.2015.1031109] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Following the approval of sorafenib as the first systemic agent for treatment of advanced hepatocellular carcinoma (HCC), there have been an increasing number of targeted treatments under testing for the cancer. However, most of the recently published drug trials in HCC failed to produce remarkable results. The researchers are actively pursuing novel therapeutic targets as well as predictive biomarker for treatment of HCC. AREAS COVERED This review discusses a number of potential novel targets for drug development of HCC. Focus is put on the underlying rationale for therapeutic development of the target and the possibility of using a predictive biomarker to select patients for drug testing. EXPERT OPINION Future direction of drug development will be discussed. Notably, a clinical trial on drug testing in HCC should be shifted from all-comers approach to selected populations based on underlying viral etiology and molecular targets. A study to evaluate predictive biomarker is crucial to the development of targeted agents for HCC. Design of clinical trials on HCC should introduce measures to encourage acquisition of tumor and plasma samples for biomarker development.
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Affiliation(s)
- Stephen L Chan
- The Chinese University of Hong Kong, Hong Kong Cancer Institute and Prince of Wales Hospital, State Key Laboratory of Oncology in South China, Sir YK Pao Center for Cancer, Department of Clinical Oncology , Hong Kong , China +852 2632 2118 ; +852 2648 7097 ;
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39
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Liu WY, Xie DM, Zhu GQ, Huang GQ, Lin YQ, Wang LR, Shi KQ, Hu B, Braddock M, Chen YP, Zheng MH. Targeting fibroblast growth factor 19 in liver disease: a potential biomarker and therapeutic target. Expert Opin Ther Targets 2015; 19:675-685. [PMID: 25547779 DOI: 10.1517/14728222.2014.997711] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Fibroblast growth factor 19 (FGF19) is a member of the hormone-like FGF family and has activity as an ileum-derived postprandial hormone. It shares high binding affinity with β-Klotho and together with the FGF receptor (FGFR) 4, is predominantly targeted to the liver. The main function of FGF19 in metabolism is the negative control of bile acid synthesis, promotion of glycogen synthesis, lipid metabolism and protein synthesis. AREAS COVERED Drawing on in vitro and in vivo studies, this review discusses FGF19 and some underlying mechanisms of action of FGF19 as an endocrine hormone in several liver diseases. The molecular pathway of the FGF19-FGFR4 axis in non-alcoholic liver disease and hepatocellular carcinoma are discussed. Furthermore, definition of function and pharmacological effects of FGF19 for liver disease are also presented. EXPERT OPINION A series of studies have highlighted a crucial role of FGF19 in liver disease. However, the conclusions of these studies are partly paradoxical and controversial. An understanding of the underlying biological mechanisms which may explain inconsistent findings is especially important for consideration of potential biomarker strategies and an exploration of the putative therapeutic efficacy of FGF19 for human liver disease.
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Affiliation(s)
- Wen-Yue Liu
- The First Affiliated Hospital of Wenzhou Medical University, Liver Research Center, Department of Infection and Liver Diseases , No. 2 Fuxue Lane, Wenzhou 325000 , China +86 577 88078232 ; +86 577 88078262 ;
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Chen H, Shen DP, Zhang ZZ, Liu JH, Shen YY, Ni XZ. Fibroblast growth factor receptor 4 protein expression and clinicopathological features in gastric cancer. World J Gastroenterol 2015; 21:1838-1844. [PMID: 25684949 PMCID: PMC4323460 DOI: 10.3748/wjg.v21.i6.1838] [Citation(s) in RCA: 10] [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: 04/17/2014] [Revised: 08/04/2014] [Accepted: 09/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate fibroblast growth factor receptor 4 (FGFR4) protein expression in Chinese patients with resectable gastric cancer (GC) and the association with clinicopathological characteristics and survival.
METHODS: One hundred and seventy-five GC patients who underwent curative surgical procedures were enrolled in this study. The protein expression of FGFR4 in formalin-fixed, paraffin-embedded (FFPE) GC tissues was determined by immunohistochemical (IHC) analysis. Patient clinicopathological data and survival information were also collected and χ2 statistical analysis was performed to analyze FGFR4 protein expression in the subgroups with differing clinicopathological characteristics including; gender, age, tumor location, differentiation, tumor-node-metastasis stage, macroscopic type, depth of invasion, lymph node metastases, distant metastasis, neural invasion and vascular invasion. Furthermore, some common molecular markers of GC in our cancer center, including p53, p27, topoisomerase IIα (Topo IIα) were also determined by IHC and their association with FGFR4 protein expression evaluated. The probability of survival for different subgroups with different clinicopathological characteristics was calculated using the Kaplan-Meier method and survival curves plotted using the log rank test.
RESULTS: Seventy seven cases (44%) were found to have high expression of FGFR4 protein. Significantly different FGFR4 expression was observed between gastric cancers with differing expression of Topo IIα (log rank χ2 = 9.4760, P = 0.0236). No significant differences were observed between subgroups defined by any of the other clinicopathological characteristics. The median survival time of the FGFR4 high expression (77 cases) and low expression groups (98 cases) was 27 mo and 39 mo, respectively. The five-year survival rates and median survival times of gastric cancers with high FGFR4 expression were worse than those with low expression (30.8% vs 39.2%, 27 mo vs 39 mo), respectively, however, no significant difference was observed in survival time (log rank χ2 = 1.0477, P = 0.3060). Survival analysis revealed that high expression of FGFR4 was a predictor of poor outcome in GC patients if the tumor was small (less than or equal to 3 cm in size) (log rank χ2 = 5.5033, P = 0.0190), well differentiated (log rank χ2 = 7.9757, P = 0.0047), and of T1 or T2 stage invasion depth (log rank χ2 = 4.8827, P = 0.0271).
CONCLUSION: Our results suggest that high tumor expression of FGFR4 protein is not an independent risk factor for GC cancer initiation, but is a useful prognostic marker for GC patients when the tumor is relatively small, well differentiated, or in the early stages of invasion.
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Tucker JA, Klein T, Breed J, Breeze AL, Overman R, Phillips C, Norman RA. Structural insights into FGFR kinase isoform selectivity: diverse binding modes of AZD4547 and ponatinib in complex with FGFR1 and FGFR4. Structure 2014; 22:1764-1774. [PMID: 25465127 DOI: 10.1016/j.str.2014.09.019] [Citation(s) in RCA: 89] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2014] [Revised: 09/19/2014] [Accepted: 09/24/2014] [Indexed: 01/01/2023]
Abstract
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases has been implicated in a wide variety of cancers. Despite a high level of sequence homology in the ATP-binding site, the majority of reported inhibitors are selective for the FGFR1-3 isoforms and display much reduced potency toward FGFR4, an exception being the Bcr-Abl inhibitor ponatinib. Here we present the crystal structure of the FGFR4 kinase domain and show that both FGFR1 and FGFR4 kinase domains in complex with ponatinib adopt a DFG-out activation loop conformation. Comparison with the structure of FGFR1 in complex with the candidate drug AZD4547, combined with kinetic characterization of the binding of ponatinib and AZD4547 to FGFR1 and FGFR4, sheds light on the observed differences in selectivity profiles and provides a rationale for developing FGFR4-selective inhibitors.
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Affiliation(s)
- Julie A Tucker
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Tobias Klein
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Jason Breed
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Alexander L Breeze
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Ross Overman
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Chris Phillips
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK
| | - Richard A Norman
- Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
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