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Long L, Zhang H, Zhou Z, Duan L, Fan D, Wang R, Xu S, Qiao D, Zhu W. Pyrrole-containing hybrids as potential anticancer agents: An insight into current developments and structure-activity relationships. Eur J Med Chem 2024; 273:116470. [PMID: 38762915 DOI: 10.1016/j.ejmech.2024.116470] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 04/28/2024] [Accepted: 04/29/2024] [Indexed: 05/21/2024]
Abstract
Cancer poses a significant threat to human health. Therefore, it is urgent to develop potent anti-cancer drugs with excellent inhibitory activity and no toxic side effects. Pyrrole and its derivatives are privileged heterocyclic compounds with significant diverse pharmacological effects. These compounds can target various aspects of cancer cells and have been applied in clinical settings or are undergoing clinical trials. As a result, pyrrole has emerged as a promising drug scaffold and has been further probed to get novel entities for the treatment of cancer. This article reviews recent research progress on anti-cancer drugs containing pyrrole. It focuses on the mechanism of action, biological activity, and structure-activity relationships of pyrrole derivatives, aiming to assist in designing and synthesizing innovative pyrrole-based anti-cancer compounds.
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Affiliation(s)
- Li Long
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China
| | - Han Zhang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China
| | - ZhiHui Zhou
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China
| | - Lei Duan
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China
| | - Dang Fan
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China
| | - Ran Wang
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China
| | - Shan Xu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China.
| | - Dan Qiao
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China.
| | - Wufu Zhu
- Jiangxi Provincial Key Laboratory of Drug Design and Evaluation, School of Pharmacy, Jiangxi Science & Technology Normal University, 605 Fenglin Road, Nanchang, Jiangxi, 330013, China.
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Khoumeri O, Hutter S, Primas N, Castera-Ducros C, Carvalho S, Wyllie S, Efrit ML, Fayolle D, Since M, Vanelle P, Verhaeghe P, Azas N, El-Kashef H. Synthesis of Nitrostyrylthiazolidine-2,4-dione Derivatives Displaying Antileishmanial Potential. Pharmaceuticals (Basel) 2024; 17:878. [PMID: 39065730 PMCID: PMC11280390 DOI: 10.3390/ph17070878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/17/2024] [Accepted: 07/01/2024] [Indexed: 07/28/2024] Open
Abstract
A series of 61 thiazolidine-2,4-diones bearing a styryl group at position 5 was synthesized in 2-5 steps and their structure was proved by elemental and spectral analyses. The compounds obtained were evaluated in vitro against the promastigote stage of the kinetoplastid parasite Leishmania infantum and the human HepG2 cell line, to determine selectivity indices and to compare their activities with those of antileishmanial reference drugs. The study of structure-activity relationships indicated the potential of some derivatives bearing a nitro group on the phenyl ring, especially when located at the meta position. Thus, among the tested series, compound 14c appeared as a hit compound with good antileishmanial activity (EC50 = 7 µM) and low cytotoxicity against both the hepatic HepG2 and macrophage THP-1 human cell lines (CC50 = 101 and 121 µM, respectively), leading to good selectivity indices (respectively, 14 and 17), in comparison with the reference antileishmanial drug compound miltefosine (EC50 = 3.3 µM, CC50 = 85 and 30 µM, SI = 26 and 9). Regarding its mechanism of action, among several possibilities, it was demonstrated that compound 14c is a prodrug bioactivated, predominantly by L. donovani nitroreductase 1, likely leading to the formation of cytotoxic metabolites that form covalent adducts in the parasite. Finally, compound 14c is lipophilic (measured CHI LogD7.7 = 2.85) but remains soluble in water (measured PBS solubility at pH7.4 = 16 µM), highlighting the antileishmanial potential of the nitrostyrylthiazolidine-2,4-dione scaffold.
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Affiliation(s)
- Omar Khoumeri
- Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France; (O.K.); (C.C.-D.); (P.V.)
| | - Sébastien Hutter
- IHU Méditerranée Infection, UMR RITMES, TEAM-VEPTE, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (S.H.); (N.A.)
| | - Nicolas Primas
- Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France; (O.K.); (C.C.-D.); (P.V.)
- Service Central de la Qualité et de l’Information Pharmaceutiques, Hôpital de la Conception, AP-HM, 147 Boulevard Baille, 13005 Marseille, France
| | - Caroline Castera-Ducros
- Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France; (O.K.); (C.C.-D.); (P.V.)
- Service Central de la Qualité et de l’Information Pharmaceutiques, Hôpital de la Conception, AP-HM, 147 Boulevard Baille, 13005 Marseille, France
| | - Sandra Carvalho
- Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; (S.C.); (S.W.)
| | - Susan Wyllie
- Wellcome Centre for Anti-Infectives Research, School of Life Sciences, University of Dundee, Dow Street, Dundee DD1 5EH, UK; (S.C.); (S.W.)
| | - Mohamed Lotfi Efrit
- Laboratoire de Synthèse Organique et Hétérocyclique Sélective-Evaluation D’activité Biologique, LR17ES01, Faculté des Sciences de Tunis, Université de Tunis El Manar, Campus Universitaire, Tunis 2092, Tunisia;
| | - Dimitri Fayolle
- Normandie Université, UNICAEN, CERMN, DruiD Platform, Boulevard Becquerel, 14000 Caen, France; (D.F.); (M.S.)
| | - Marc Since
- Normandie Université, UNICAEN, CERMN, DruiD Platform, Boulevard Becquerel, 14000 Caen, France; (D.F.); (M.S.)
| | - Patrice Vanelle
- Team Pharmaco-Chimie Radicalaire, Faculté de Pharmacie, Aix Marseille University, CNRS, ICR UMR 7273, 27 Boulevard Jean Moulin, CS30064, CEDEX 05, 13385 Marseille, France; (O.K.); (C.C.-D.); (P.V.)
- Service Central de la Qualité et de l’Information Pharmaceutiques, Hôpital de la Conception, AP-HM, 147 Boulevard Baille, 13005 Marseille, France
| | - Pierre Verhaeghe
- CNRS, Département de Pharmacochimie Moléculaire UMR 5063, University Grenoble Alpes, 38041 Grenoble, France;
- LCC-CNRS, UPR8241, Laboratoire de Chimie de Coordination, Université de Toulouse, CNRS, UPS, 31400 Toulouse, France
| | - Nadine Azas
- IHU Méditerranée Infection, UMR RITMES, TEAM-VEPTE, Aix Marseille University, 19-21 Boulevard Jean Moulin, 13005 Marseille, France; (S.H.); (N.A.)
| | - Hussein El-Kashef
- Chemistry Department, Faculty of Science, Assiut University, Assiut 71516, Egypt
- Faculty of Pharmacy, Sphinx University, Regional Road, New Assiut 71515, Egypt
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Jin F, Lin Y, Yuan W, Wu S, Yang M, Ding S, Liu J, Chen Y. Recent advances in c-Met-based dual inhibitors in the treatment of cancers. Eur J Med Chem 2024; 272:116477. [PMID: 38733884 DOI: 10.1016/j.ejmech.2024.116477] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2024] [Revised: 05/03/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024]
Abstract
The cellular-mesenchymal epithelial transition factor (c-Met) is a receptor tyrosine kinase (RTK) located on the 7q31 locus encoding the Met proto-oncogene and plays a critical role in regulating cell proliferation, metastasis, differentiation, and apoptosis through various signaling pathways. However, its aberrant activation and overexpression have been implicated in many human cancers. Therefore, c-Met is a promising target for cancer treatment. However, the anticancer effect of selective single-targeted drugs is limited due to the complexity of the signaling system and the involvement of different proteins and enzymes. After inhibiting one pathway, signal molecules can be transmitted through other pathways, resulting in poor efficacy of single-targeted drug therapy. Dual inhibitors that simultaneously block c-Met and another factor can significantly improve efficacy and overcome some of the shortcomings of single-target inhibitors, including drug resistance. In this review, We introduced c-Met kinase and the synergism between c-Met and other anti-tumor targets, then dual-target inhibitors based on c-Met for the treatment of cancers were summarized and their design concepts and structure-activity relationships (SARs) were discussed elaborately, providing a valuable insight for the further development of novel c-Met-based dual inhibitors.
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Affiliation(s)
- Fanqi Jin
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Yihan Lin
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Weidong Yuan
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Shuang Wu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Min Yang
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China
| | - Shi Ding
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China
| | - Ju Liu
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China.
| | - Ye Chen
- College of Pharmacy of Liaoning University, Shenyang, Liaoning, 110036, PR China; API Engineering Technology Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China; Small Molecular Targeted Drug R&D Engineering Research Center of Liaoning Province, Shenyang, Liaoning, 110036, PR China.
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Liu Z, Chen L, Zhang J, Yang J, Xiao X, Shan L, Mao W. Recent discovery and development of AXL inhibitors as antitumor agents. Eur J Med Chem 2024; 272:116475. [PMID: 38714043 DOI: 10.1016/j.ejmech.2024.116475] [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: 02/01/2024] [Revised: 04/30/2024] [Accepted: 05/01/2024] [Indexed: 05/09/2024]
Abstract
AXL, a receptor tyrosine kinase (RTK), plays a pivotal role in various cellular functions. It is primarily involved in processes such as epithelial-mesenchymal transition (EMT) in tumor cells, angiogenesis, apoptosis, immune regulation, and chemotherapy resistance mechanisms. Therefore, targeting AXL is a promising therapeutic approach for the treatment of cancer. AXL inhibitors that have entered clinical trials, such as BGB324(1), have shown promising efficacy in the treatment of melanoma and non-small cell lung cancer. Additionally, novel AXL-targeted drugs, such as AXL degraders, offer a potential solution to overcome the limitations of traditional small-molecule AXL inhibitors targeting single pathways. We provide an overview of the structure and biological functions of AXL, discusses its correlation with various cancers, and critically analyzes the structure-activity relationship of AXL small-molecule inhibitors in cellular contexts. Additionally, we summarize multiple research and development strategies, offering insights for the future development of innovative AXL inhibitors.
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Affiliation(s)
- Zihang Liu
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China
| | - Li Chen
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China; Department of Pharmacy, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610072, Sichuan, China
| | - Jifa Zhang
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Jun Yang
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China
| | - Xue Xiao
- Department of Obstetrics & Gynecology, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
| | - Lianhai Shan
- School of Life Science and Engineering, Southwest Jiaotong University, Chengdu, 610031, Sichuan, China.
| | - Wuyu Mao
- Department of Respiratory and Critical Care Medicine, Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-Related Molecular Network, Precision Medicine Key Laboratory of Sichuan Province & Precision Medicine Center, State Key Laboratory of Respiratory Health and Multimorbidity, Laboratory of Neuro-system and Multimorbidity, West China Hospital, Sichuan University, Chengdu, 610041, Sichuan, China.
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Aboshouk DR, Youssef MA, Bekheit MS, Hamed AR, Girgis AS. Antineoplastic indole-containing compounds with potential VEGFR inhibitory properties. RSC Adv 2024; 14:5690-5728. [PMID: 38362086 PMCID: PMC10866129 DOI: 10.1039/d3ra08962b] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Accepted: 01/29/2024] [Indexed: 02/17/2024] Open
Abstract
Cancer is one of the most significant health challenges worldwide. Various techniques, tools and therapeutics/materials have been developed in the last few decades for the treatment of cancer, together with great interest, funding and efforts from the scientific society. However, all the reported studies and efforts seem insufficient to combat the various types of cancer, especially the advanced ones. The overexpression of tyrosine kinases is associated with cancer proliferation and/or metastasis. VEGF, an important category of tyrosine kinases, and its receptors (VEGFR) are hyper-activated in different cancers. Accordingly, they are known as important factors in the angiogenesis of different tumors and are considered in the development of effective therapeutic approaches for controlling many types of cancer. In this case, targeted therapeutic approaches are preferable to the traditional non-selective approaches to minimize the side effects and drawbacks associated with treatment. Several indole-containing compounds have been identified as effective agents against VEGFR. Herein, we present a summary of the recent indolyl analogs reported within the last decade (2012-2023) with potential antineoplastic and VEGFR inhibitory properties. The most important drugs, natural products, synthesized potent compounds and promising hits/leads are highlighted. Indoles functionalized and conjugated with various heterocycles beside spiroindoles are also considered.
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Affiliation(s)
- Dalia R Aboshouk
- Department of Pesticide Chemistry, National Research Centre Dokki Giza 12622 Egypt
| | - M Adel Youssef
- Department of Chemistry, Faculty of Science, Helwan University Helwan Egypt
| | - Mohamed S Bekheit
- Department of Pesticide Chemistry, National Research Centre Dokki Giza 12622 Egypt
| | - Ahmed R Hamed
- Chemistry of Medicinal Plants Department, National Research Centre Dokki Giza 12622 Egypt
| | - Adel S Girgis
- Department of Pesticide Chemistry, National Research Centre Dokki Giza 12622 Egypt
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Pidkovka N, Belkhiri A. Altered expression of AXL receptor tyrosine kinase in gastrointestinal cancers: a promising therapeutic target. Front Oncol 2023; 13:1079041. [PMID: 37469409 PMCID: PMC10353021 DOI: 10.3389/fonc.2023.1079041] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 05/31/2023] [Indexed: 07/21/2023] Open
Abstract
Gastrointestinal (GI) cancers that include all cancers of the digestive tract organs are generally associated with obesity, lack of exercising, smoking, poor diet, and heavy alcohol consumption. Treatment of GI cancers typically involves surgery followed by chemotherapy and/or radiation. Unfortunately, intrinsic or acquired resistance to these therapies underscore the need for more effective targeted therapies that have been proven in other malignancies. The aggressive features of GI cancers share distinct signaling pathways that are connected to each other by the overexpression and activation of AXL receptor tyrosine kinase. Several preclinical and clinical studies involving anti-AXL antibodies and small molecule AXL kinase inhibitors to test their efficacy in solid tumors, including GI cancers, have been recently carried out. Therefore, AXL may be a promising therapeutic target for overcoming the shortcomings of standard therapies in GI cancers.
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Affiliation(s)
- Nataliya Pidkovka
- Department of Health Science, South College, Nashville, TN, United States
| | - Abbes Belkhiri
- Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States
- Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, United States
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Zhang D, Zhao Y, You X, He S, Li E. Repurposing Axl Kinase Inhibitors for the Treatment of Respiratory Syncytial Virus Infection. Antimicrob Agents Chemother 2023; 67:e0148722. [PMID: 36853000 PMCID: PMC10019287 DOI: 10.1128/aac.01487-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2022] [Accepted: 02/01/2023] [Indexed: 03/01/2023] Open
Abstract
Respiratory syncytial virus (RSV) infection persists as a common pathogen of pulmonary infection in infants and in the elderly with high morbidity and mortality. However, no specific therapeutics are available. Axl, a member of the TAM (Tyro3, Axl, and Mertk) family receptor kinases, is a pleiotropic inhibitor of the innate immune response and functions as a negative regulator of interferon pathway activation. In this report, we investigated Axl inhibitors for their effects against RSV infection. Axl inhibition with kinase inhibitors, including BMS-777607, R428, and TP-0903, or Axl ablation resulted in a significant reduction of RSV infection in cell-based assays. In an animal model of pulmonary RSV infection, treatment with BMS-777607, R428, or TP-0903 ameliorated pulmonary pathology with a significant reduction of RSV titers in the lung tissues and, consequently, decreased the expression of proinflammatory genes. The host promotes ISG expression for the antiviral response and for viral clearance. We found that Axl inhibition led to more robust IFN-β expression and antiviral gene induction. Thus, the results of this study imply that Axl kinase inhibitors may possess a broad spectrum of antiviral effects by promoting ISG expression.
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Affiliation(s)
- Dan Zhang
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Yuanhui Zhao
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu, China
- Yancheng Medical Research Center, The Affiliated Yancheng People's 1st Hospital of Nanjing University Medical School, Yancheng, Jiangsu, China
| | - Xiaoxin You
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu, China
| | - Susu He
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu, China
- Yancheng Medical Research Center, The Affiliated Yancheng People's 1st Hospital of Nanjing University Medical School, Yancheng, Jiangsu, China
| | - Erguang Li
- State Key Laboratory of Pharmaceutical Biotechnology, Medical School, Nanjing University, Nanjing, China
- Jiangsu Key Laboratory of Molecular Medicine, Medical School, Nanjing University, Nanjing, Jiangsu, China
- Institute of Medical Virology, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, Jiangsu, China
- Shenzhen Research Institute of Nanjing University, Shenzhen, China
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8
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Mei C, Gong W, Wang X, Lv Y, Zhang Y, Wu S, Zhu C. Anti-angiogenic therapy in ovarian cancer: Current understandings and prospects of precision medicine. Front Pharmacol 2023; 14:1147717. [PMID: 36959862 PMCID: PMC10027942 DOI: 10.3389/fphar.2023.1147717] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Accepted: 02/23/2023] [Indexed: 03/09/2023] Open
Abstract
Ovarian cancer (OC) remains the most fatal disease of gynecologic malignant tumors. Angiogenesis refers to the development of new vessels from pre-existing ones, which is responsible for supplying nutrients and removing metabolic waste. Although not yet completely understood, tumor vascularization is orchestrated by multiple secreted factors and signaling pathways. The most central proangiogenic signal, vascular endothelial growth factor (VEGF)/VEGFR signaling, is also the primary target of initial clinical anti-angiogenic effort. However, the efficiency of therapy has so far been modest due to the low response rate and rapidly emerging acquiring resistance. This review focused on the current understanding of the in-depth mechanisms of tumor angiogenesis, together with the newest reports of clinical trial outcomes and resistance mechanism of anti-angiogenic agents in OC. We also emphatically summarized and analyzed previously reported biomarkers and predictive models to describe the prospect of precision therapy of anti-angiogenic drugs in OC.
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Affiliation(s)
- Chao Mei
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weijing Gong
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Xu Wang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yongning Lv
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sanlan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China
| | - Chunqi Zhu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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9
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Tsukamoto S, Sugi NH, Nishibata K, Nakazawa Y, Ito D, Fukushima S, Nakagawa T, Ichikawa K, Kato Y, Kakiuchi D, Goto A, Itoh-Yagi M, Aota T, Inoue S, Yamane Y, Murai N, Azuma H, Nagao S, Sasai K, Akagi T, Imai T, Matsui J, Matsushima T. ER-851, a Novel Selective Inhibitor of AXL, Overcomes Resistance to Antimitotic Drugs. Mol Cancer Ther 2023; 22:12-24. [PMID: 36279567 DOI: 10.1158/1535-7163.mct-21-0879] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 08/11/2022] [Accepted: 10/19/2022] [Indexed: 01/04/2023]
Abstract
Innate and adaptive resistance to cancer therapies, such as chemotherapies, molecularly targeted therapies, and immune-modulating therapies, is a major issue in clinical practice. Subpopulations of tumor cells expressing the receptor tyrosine kinase AXL become enriched after treatment with antimitotic drugs, causing tumor relapse. Elevated AXL expression is closely associated with drug resistance in clinical samples, suggesting that AXL plays a pivotal role in drug resistance. Although several molecules with AXL inhibitory activity have been developed, none have sufficient activity and selectivity to be clinically effective when administered in combination with a cancer therapy. Here, we report a novel small molecule, ER-851, which is a potent and highly selective AXL inhibitor. To investigate resistance mechanisms and identify driving molecules, we conducted a comprehensive gene expression analysis of chemoresistant tumor cells in mouse xenograft models of genetically engineered human lung cancer and human triple-negative breast cancer. Consistent with the effect of AXL knockdown, cotreatment of ER-851 and antimitotic drugs produced an antitumor effect and prolonged relapse-free survival in the mouse xenograft model of human triple-negative breast cancer. Importantly, when orally administered to BALB/c mice, this compound did not induce retinal toxicity, a known side effect of chronic MER inhibition. Together, these data strongly suggest that AXL is a therapeutic target for overcoming drug resistance and that ER-851 is a promising candidate therapeutic agent for use against AXL-expressing antimitotic-resistant tumors.
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Affiliation(s)
- Shuntaro Tsukamoto
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Naoko Hata Sugi
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Kyoko Nishibata
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Youya Nakazawa
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Daisuke Ito
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Sayo Fukushima
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Takayuki Nakagawa
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Kenji Ichikawa
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Yu Kato
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Dai Kakiuchi
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Aya Goto
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | | | - Tomoki Aota
- hhc Data Creation Center, Eisai Co., Ltd., Bunkyo-ku, Tokyo, Japan
| | - Satoshi Inoue
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Yoshinobu Yamane
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Norio Murai
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Hiroshi Azuma
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Satoshi Nagao
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
| | - Ken Sasai
- KAN Research Institute, Inc., Kobe-shi, Hyogo, Japan
| | - Tsuyoshi Akagi
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan.,KAN Research Institute, Inc., Kobe-shi, Hyogo, Japan
| | - Toshio Imai
- KAN Research Institute, Inc., Kobe-shi, Hyogo, Japan
| | - Junji Matsui
- Tsukuba Research Laboratories, Eisai Co., Ltd., Tsukuba-shi, Ibaraki, Japan
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10
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Malvankar C, Kumar D. AXL kinase inhibitors- A prospective model for medicinal chemistry strategies in anticancer drug discovery. Biochim Biophys Acta Rev Cancer 2022; 1877:188786. [PMID: 36058379 DOI: 10.1016/j.bbcan.2022.188786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 07/19/2022] [Accepted: 08/23/2022] [Indexed: 12/14/2022]
Abstract
Deviant expressions of the tyrosine kinase AXL receptor are strongly correlated with a plethora of malignancies. Henceforth, the topic of targeting AXL is beginning to gain prominence due to mounting evidence of the protein's substantial connection to poor prognosis and treatment resistance. This year marked a milestone in clinical testing for AXL as an anti-carcinogenic target, with the start of the first AXL-branded inhibitor study. It is critical to emphasize that AXL is a primary and secondary target in various kinase inhibitors that have been approved or are on the verge of being approved while interpreting the present benefits and future potential effects of AXL suppression in the clinical setting. Several research arenas across the globe resolutely affirm the crucial significance of AXL receptors in the case study of several pathophysiologies including AML, prostate cancer, and breast cancer. This review endeavors to delve deeply into the biological, chemical, and structural features of AXL kinase; primary AXL inhibitors that target the enzyme (either purposefully or unintentionally); and the prospects and barriers for turning AXL inhibitors into a feasible treatment alternative. Furthermore, we analyse the co-crystal structure of AXL, which remains extensively unexplored, as well as the mutations of AXL that may be valuable in the development of novel inhibitors in the upcoming future and take a comprehensive look at the medicinal chemistry of AXL inhibitors of recent years.
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Affiliation(s)
- Chinmay Malvankar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra 411038, India
| | - Dileep Kumar
- Poona College of Pharmacy, Bharati Vidyapeeth (Deemed to be) University, Pune, Maharashtra 411038, India; Department of Entomology, University of California, Davis, One Shields Ave, Davis, CA 95616, USA; UC Davis Comprehensive Cancer Center, University of California, Davis, One Shields Ave, Davis, CA 95616, USA.
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11
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Receptor Tyrosine Kinases Amplified in Diffuse-Type Gastric Carcinoma: Potential Targeted Therapies and Novel Downstream Effectors. Cancers (Basel) 2022; 14:cancers14153750. [PMID: 35954414 PMCID: PMC9367326 DOI: 10.3390/cancers14153750] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 07/28/2022] [Accepted: 07/28/2022] [Indexed: 11/28/2022] Open
Abstract
Simple Summary Diffuse-type gastric carcinoma (DGC) is an aggressive subtype of gastric carcinoma with an extremely poor prognosis due to frequent peritoneal metastasis and high probability of recurrence. Its pathogenesis is poorly understood, and consequently, no effective molecular targeted therapy is available. The importance of oncogenic receptor tyrosine kinase (RTK) signaling has been recently demonstrated in the malignant progression of DGC. In particular, RTK gene amplification appears to accelerate peritoneal metastasis. In this review, we provide an overview of RTK gene amplification in DGC and the potential of related targeted therapies. Abstract Gastric cancer (GC) is a major cause of cancer-related death worldwide. Patients with an aggressive subtype of GC, known as diffuse-type gastric carcinoma (DGC), have extremely poor prognoses. DGC is characterized by rapid infiltrative growth, massive desmoplastic stroma, frequent peritoneal metastasis, and high probability of recurrence. These clinical features and progression patterns of DGC substantially differ from those of other GC subtypes, suggesting the existence of specific oncogenic signals. The importance of gene amplification and the resulting aberrant activation of receptor tyrosine kinase (RTK) signaling in the malignant progression of DGC is becoming apparent. Here, we review the characteristics of RTK gene amplification in DGC and its importance in peritoneal metastasis. These insights may potentially lead to new targeted therapeutics.
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12
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Two-Front War on Cancer-Targeting TAM Receptors in Solid Tumour Therapy. Cancers (Basel) 2022; 14:cancers14102488. [PMID: 35626092 PMCID: PMC9140196 DOI: 10.3390/cancers14102488] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 05/14/2022] [Accepted: 05/17/2022] [Indexed: 02/04/2023] Open
Abstract
Simple Summary In recent years, many studies have shown the importance of TAM kinases in both normal and neoplastic cells. In this review, we present and discuss the role of the TAM family (AXL, MERTK, TYRO3) of receptor tyrosine kinases (RTKs) as a dual target in cancer, due to their intrinsic roles in tumour cell survival, migration, chemoresistance, and their immunosuppressive roles in the tumour microenvironment. This review presents the potential of TAMs as emerging therapeutic targets in cancer treatment, focusing on the distinct structures of TAM receptor tyrosine kinases. We analyse and compare different strategies of TAM inhibition, for a full perspective of current and future battlefields in the war with cancer. Abstract Receptor tyrosine kinases (RTKs) are transmembrane receptors that bind growth factors and cytokines and contain a regulated kinase activity within their cytoplasmic domain. RTKs play an important role in signal transduction in both normal and malignant cells, and their encoding genes belong to the most frequently affected genes in cancer cells. The TAM family proteins (TYRO3, AXL, and MERTK) are involved in diverse biological processes: immune regulation, clearance of apoptotic cells, platelet aggregation, cell proliferation, survival, and migration. Recent studies show that TAMs share overlapping functions in tumorigenesis and suppression of antitumour immunity. MERTK and AXL operate in innate immune cells to suppress inflammatory responses and promote an immunosuppressive tumour microenvironment, while AXL expression correlates with epithelial-to-mesenchymal transition, metastasis, and motility in tumours. Therefore, TAM RTKs represent a dual target in cancer due to their intrinsic roles in tumour cell survival, migration, chemoresistance, and their immunosuppressive roles in the tumour microenvironment (TME). In this review, we discuss the potential of TAMs as emerging therapeutic targets in cancer treatment. We critically assess and compare current approaches to target TAM RTKs in solid tumours and the development of new inhibitors for both extra- and intracellular domains of TAM receptor kinases.
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13
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Zheng J, Zhang W, Li L, He Y, Wei Y, Dang Y, Nie S, Guo Z. Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review. Front Chem 2022; 10:860985. [PMID: 35494629 PMCID: PMC9046545 DOI: 10.3389/fchem.2022.860985] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/28/2022] [Indexed: 12/23/2022] Open
Abstract
Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In the past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing the biological basis of FGF/FGFR signaling. It then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of small-molecule-based therapies of different modalities. It ends with our perspectives for the development of novel FGFR inhibitors.
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Affiliation(s)
| | | | | | | | | | | | - Shenyou Nie
- Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
| | - Zufeng Guo
- Center for Novel Target and Therapeutic Intervention, Institute of Life Sciences, Chongqing Medical University, Chongqing, China
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14
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Lotsberg ML, Davidsen KT, D’Mello Peters S, Haaland GS, Rayford A, Lorens JB, Engelsen AST. The Role of AXL Receptor Tyrosine Kinase in Cancer Cell Plasticity and Therapy Resistance. BIOMARKERS OF THE TUMOR MICROENVIRONMENT 2022:307-327. [DOI: 10.1007/978-3-030-98950-7_18] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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15
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Yan D, Earp HS, DeRyckere D, Graham DK. Targeting MERTK and AXL in EGFR Mutant Non-Small Cell Lung Cancer. Cancers (Basel) 2021; 13:5639. [PMID: 34830794 PMCID: PMC8616094 DOI: 10.3390/cancers13225639] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2021] [Revised: 11/09/2021] [Accepted: 11/10/2021] [Indexed: 12/20/2022] Open
Abstract
MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations.
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Affiliation(s)
- Dan Yan
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; (D.Y.); (D.D.)
| | - H. Shelton Earp
- UNC Lineberger Comprehensive Cancer Center, Department of Medicine, Chapel Hill, NC 27599, USA;
- Department of Pharmacology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Deborah DeRyckere
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; (D.Y.); (D.D.)
| | - Douglas K. Graham
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Department of Pediatrics, Emory University, Atlanta, GA 30322, USA; (D.Y.); (D.D.)
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16
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Huang D, Yang J, Zhang Q, Wang G, Zhang Z, Zhang Y, Li J. Structure-guided design and development of novel N-phenylpyrimidin-2-amine derivatives as potential c-Met inhibitors. Eur J Med Chem 2021; 223:113648. [PMID: 34175535 DOI: 10.1016/j.ejmech.2021.113648] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 06/10/2021] [Accepted: 06/11/2021] [Indexed: 12/20/2022]
Abstract
The HGF/Met signaling pathway is over-expressed in many types of cancers and closely related to oncogenesis and metastasis. Thus, we developed novel N-phenylpyrimidin-2-amine derivatives to test their inhibitory activities towards c-Met kinase, and most of the compounds (15a-i, 15o-r, 20 and 34a-c) could inhibit the target with IC50 values from 550.8 nM to 15.0 nM. Subsequently, compound 15b, 15d, 15f, 15i, 15o, 15r, 20, 34a and 34b also showed high antiproliferative activities in c-Met sensitive tumor cell lines (PC-3, Panc-1, HepG2, HCT116 and Caki-1) with IC50 values from 0.53 to 1.37 μM. The lead compound 34a displayed outstanding c-Met inhibitory activity (IC50: 15.0 nM) and antiproliferative activities. Furthermore, 34a also performed favorable pharmacokinetic properties in mice (F%: 59.3) and an acceptable safety profile in preclinical studies. Further docking studies showed a common interaction of 34a with c-Met at the ATP-binding site, which indicated that 34a could be a potential candidate for c-Met inhibitors.
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Affiliation(s)
- Daowei Huang
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China
| | - Jixia Yang
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, 050018, China
| | - Qingwei Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China
| | - Guan Wang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China
| | - Zixue Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China
| | - Yue Zhang
- School of Chemical and Pharmaceutical Engineering, Hebei University of Science and Technology, Shijiazhuang, 050018, China.
| | - Jianqi Li
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, Shanghai, 201203, China; Shanghai Engineering Research Center of Pharmaceutical Process, Shanghai, 201203, China.
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17
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Ooki A, Yamaguchi K. The beginning of the era of precision medicine for gastric cancer with fibroblast growth factor receptor 2 aberration. Gastric Cancer 2021; 24:1169-1183. [PMID: 34398359 DOI: 10.1007/s10120-021-01235-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2021] [Accepted: 08/11/2021] [Indexed: 02/07/2023]
Abstract
Despite recent advances in the systemic treatment of metastatic gastric cancer (GC), prognostic outcomes remain poor. Considerable research effort has been invested in characterizing the genomic landscape of GC and identifying potential therapeutic targets. FGFR2 is one of the most attractive targets because aberrations in this gene are frequently associated with GC, particularly the diffuse type in Lauren's classification, which confers an unfavorable prognosis. Based on the preclinical data, the FGFR2 signaling pathway plays a key role in the development and progression of GC, and several FGFR inhibitors have been clinically assessed. However, the lack of robust treatment efficacy has hampered precision medicine for patients with FGFR2-aberrant GC. Recently, the clinical benefits of the FGFR2-IIIb-selective monoclonal antibody bemarituzumab for FGFR2b-positive GC patients were shown in a randomized phase II FIGHT trial of bemarituzumab combined with the first-line chemotherapy. This trial demonstrates proof of concept, suggesting that FGFR2 is a relevant therapeutic target for patients with FGFR2b-positive GC and that bemarituzumab brings new hope for diffuse-type GC patients. In this review, we summarize the oncogenic roles of FGFR2 signaling and highlight the most recent advances in FGFR inhibitors based on the findings of pivotal clinical trials for patients with FGFR2-aberrant GC. Thus, the era of precision medicine for patients with FGFR2-aberrant GC will be opened.
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Affiliation(s)
- Akira Ooki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan.
| | - Kensei Yamaguchi
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo, 135-8550, Japan
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18
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Tosca EM, Gauderat G, Fouliard S, Burbridge M, Chenel M, Magni P. Modeling restoration of gefitinib efficacy by co-administration of MET inhibitors in an EGFR inhibitor-resistant NSCLC xenograft model: A tumor-in-host DEB-based approach. CPT-PHARMACOMETRICS & SYSTEMS PHARMACOLOGY 2021; 10:1396-1411. [PMID: 34708556 PMCID: PMC8592518 DOI: 10.1002/psp4.12710] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 08/02/2021] [Accepted: 08/17/2021] [Indexed: 12/19/2022]
Abstract
MET receptor tyrosine kinase inhibitors (TKIs) can restore sensitivity to gefitinib, a TKI targeting epidermal growth factor receptor (EGFR), and promote apoptosis in non-small cell lung cancer (NSCLC) models resistant to gefitinib treatment in vitro and in vivo. Several novel MET inhibitors are currently under study in different phases of development. In this work, a novel tumor-in-host modeling approach, based on the Dynamic Energy Budget (DEB) theory, was proposed and successfully applied to the context of poly-targeted combination therapies. The population DEB-based tumor growth inhibition (TGI) model well-described the effect of gefitinib and of two MET inhibitors, capmatinib and S49076, on both tumor growth and host body weight when administered alone or in combination in an NSCLC mice model involving the gefitinib-resistant tumor line HCC827ER1. The introduction of a synergistic effect in the combination DEB-TGI model allowed to capture gefitinib anticancer activity enhanced by the co-administered MET inhibitor, providing also a quantitative evaluation of the synergistic drug interaction. The model-based comparison of the two MET inhibitors highlighted that S49076 exhibited a greater anticancer effect as well as a greater ability in restoring sensitivity to gefitinib than the competitor capmatinib. In summary, the DEB-based tumor-in-host framework proposed here can be applied to routine combination xenograft experiments, providing an assessment of drug interactions and contributing to rank investigated compounds and to select the optimal combinations, based on both tumor and host body weight dynamics. Thus, the combination tumor-in-host DEB-TGI model can be considered a useful tool in the preclinical development and a significant advance toward better characterization of combination therapies.
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Affiliation(s)
- Elena M. Tosca
- Laboratory of Bioinformatics, Mathematical Modelling and Synthetic BiologyDepartment of ElectricalComputer and Biomedical EngineeringUniversità degli Studi di PaviaPaviaItaly
| | - Glenn Gauderat
- Clinical Pharmacokinetics and Pharmacometrics DivisionServierSuresnesFrance
| | - Sylvain Fouliard
- Clinical Pharmacokinetics and Pharmacometrics DivisionServierSuresnesFrance
| | - Mike Burbridge
- Center for Therapeutic Innovation in OncologyServierSuresnesFrance
- Present address:
Engitix therapeuticsLondonUK
| | - Marylore Chenel
- Clinical Pharmacokinetics and Pharmacometrics DivisionServierSuresnesFrance
- Present address:
Pharmetheus ABUppsalaSweden
| | - Paolo Magni
- Laboratory of Bioinformatics, Mathematical Modelling and Synthetic BiologyDepartment of ElectricalComputer and Biomedical EngineeringUniversità degli Studi di PaviaPaviaItaly
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19
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Therapeutic Targeting of the Gas6/Axl Signaling Pathway in Cancer. Int J Mol Sci 2021; 22:ijms22189953. [PMID: 34576116 PMCID: PMC8469858 DOI: 10.3390/ijms22189953] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Revised: 09/09/2021] [Accepted: 09/12/2021] [Indexed: 12/14/2022] Open
Abstract
Many signaling pathways are dysregulated in cancer cells and the host tumor microenvironment. Aberrant receptor tyrosine kinase (RTK) pathways promote cancer development, progression, and metastasis. Hence, numerous therapeutic interventions targeting RTKs have been actively pursued. Axl is an RTK that belongs to the Tyro3, Axl, MerTK (TAM) subfamily. Axl binds to a high affinity ligand growth arrest specific 6 (Gas6) that belongs to the vitamin K-dependent family of proteins. The Gas6/Axl signaling pathway has been implicated to promote progression, metastasis, immune evasion, and therapeutic resistance in many cancer types. Therapeutic agents targeting Gas6 and Axl have been developed, and promising results have been observed in both preclinical and clinical settings when such agents are used alone or in combination therapy. This review examines the current state of therapeutics targeting the Gas6/Axl pathway in cancer and discusses Gas6- and Axl-targeting agents that have been evaluated preclinically and clinically.
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20
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Fu J, Su X, Li Z, Deng L, Liu X, Feng X, Peng J. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 2021; 40:4625-4651. [PMID: 34145400 DOI: 10.1038/s41388-021-01863-w] [Citation(s) in RCA: 116] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal-epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.
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Affiliation(s)
- Jianjiang Fu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xiaorui Su
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Zhihua Li
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
- Department of Fetal Medicine and Prenatal Diagnosis, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ling Deng
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiawei Liu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xuancheng Feng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
| | - Juan Peng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
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21
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Inoue S, Yamane Y, Tsukamoto S, Azuma H, Nagao S, Murai N, Nishibata K, Fukushima S, Ichikawa K, Nakagawa T, Hata Sugi N, Ito D, Kato Y, Goto A, Kakiuchi D, Ueno T, Matsui J, Matsushima T. Discovery of a potent and selective Axl inhibitor in preclinical model. Bioorg Med Chem 2021; 39:116137. [PMID: 33930844 DOI: 10.1016/j.bmc.2021.116137] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Revised: 03/18/2021] [Accepted: 03/22/2021] [Indexed: 11/16/2022]
Abstract
Axl and Mer are a members of the TAM (Tyro3-Axl-Mer) family of receptor tyrosine kinases, which, when activated, can promote tumor cell survival, proliferation, migration, invasion, angiogenesis, and tumor-host interactions. Chronic inhibition of Mer leads to retinal toxicity in mice. Therefore, successful development of an Axl targeting agent requires ensuring that it is safe for prolonged treatment. Here, to clarify whether enzyme inhibition of Mer by a small molecule leads to retinal toxicity in mice, we designed and synthesized Axl/Mer inhibitors and Axl-selective inhibitors. We identified an Axl/Mer dual inhibitor 28a, which showed retinal toxicity at a dose of 100 mg/kg in mice. Subsequent derivatization of a pyridine derivative led to the discovery of a pyrimidine derivative, 33g, which selectively inhibited the activity of Axl over Mer without retinal toxicity at a dose of 100 mg/kg in mice. Additionally, the compound displayed in vivo anti-tumor effects without influencing body weight in a Ba/F3-Axl isogenic subcutaneous model.
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Affiliation(s)
- Satoshi Inoue
- Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan.
| | - Yoshinobu Yamane
- Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Shuntaro Tsukamoto
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Hiroshi Azuma
- Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Satoshi Nagao
- Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Norio Murai
- Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Kyoko Nishibata
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Sayo Fukushima
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Kenji Ichikawa
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Takayuki Nakagawa
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Naoko Hata Sugi
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Daisuke Ito
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Yu Kato
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Aya Goto
- Drug Safety, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Dai Kakiuchi
- Drug Safety, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Takashi Ueno
- Drug Metabolism and Pharmacokinetics, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Junji Matsui
- Biopharmacology, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
| | - Tomohiro Matsushima
- Medicinal Chemistry, Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba-shi, Ibaraki 300-2635, Japan
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Anti-Angiogenic Therapy: Current Challenges and Future Perspectives. Int J Mol Sci 2021; 22:ijms22073765. [PMID: 33916438 PMCID: PMC8038573 DOI: 10.3390/ijms22073765] [Citation(s) in RCA: 217] [Impact Index Per Article: 54.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 03/29/2021] [Accepted: 03/31/2021] [Indexed: 02/07/2023] Open
Abstract
Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.
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Phase I results of S49076 plus gefitinib in patients with EGFR TKI-resistant non-small cell lung cancer harbouring MET/AXL dysregulation. Lung Cancer 2021; 155:127-135. [PMID: 33798902 DOI: 10.1016/j.lungcan.2021.03.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 03/11/2021] [Indexed: 01/29/2023]
Abstract
BACKGROUND MET and AXL dysregulation is reported as a bypass mechanism driving tumour progression in non-small cell lung cancer (NSCLC) with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). This non-comparative phase I study investigated the combination of gefitinib with S49076, a MET/AXL inhibitor, in advanced EGFR TKI-resistant NSCLC patients with MET and/or AXL dysregulation. METHODS Patients received S49076 at escalating doses of 500 or 600 mg with a fixed dose of 250 mg gefitinib orally once daily in continuous 28day cycles. MET and AXL dysregulation and EGFR/T790M mutation status were centrally assessed in tumour biopsies at screening. Tumour response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST). EGFR TKI resistance mechanisms were analysed by next-generation sequencing. The clonal evolution of tumours was monitored with the analysis of circulating tumour DNA. RESULTS Of 92 pre-screened patients, 22 met the molecular inclusion criteria and 14 were included. The recommended dose was 600 mg daily S49076. Best overall responses were 2 partial responses (1 patient with MET dysregulation only, 1 MET and AXL co-dysregulation) and 8 patients with stable disease. Other potential concomitant mechanisms of resistance to EGFR TKI were identified in more than half of the included patients. CONCLUSIONS S49076 plus gefitinib demonstrated a good tolerability with limited anti-tumour activity. Due to the low number of eligible patients, no tendency in term of activity appeared in any specific molecular subset and the data did not allow for identification of AXL overexpression as an oncogenic driver.
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Studying the Binding Modes of Novel 2-Aminopyridine Derivatives as Effective and Selective c-Met Kinase Type 1 Inhibitors Using Molecular Modeling Approaches. Molecules 2020; 26:molecules26010052. [PMID: 33374386 PMCID: PMC7795969 DOI: 10.3390/molecules26010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2020] [Revised: 12/17/2020] [Accepted: 12/17/2020] [Indexed: 11/16/2022] Open
Abstract
The mesenchymal epithelial cell transforming factor c-Met, encoded by c-Met proto-oncogene and known as a high-affinity receptor for Hepatocyte Growth Factor (HGF), is one of the receptor tyrosine kinases (RTKs) members. The HGF/c-Met signaling pathway has close correlation with tumor growth, invasion and metastasis. Thus, c-Met kinase has emerged as a prominent therapeutic target for cancer drug discovery. Recently a series of novel 2-aminopyridine derivatives targeting c-Met kinase with high biological activity were reported. In this study, 3D quantitative structure-activity relationship (QSAR), molecular docking and molecular dynamics simulations (MD) were employed to research the binding modes of these inhibitors.The results show that both the atom-based and docking-based CoMFA (Q2 = 0.596, R2 = 0.950 in atom-based model and Q2 = 0.563, R2 = 0.985 in docking-based model) and CoMSIA (Q2 = 0.646, R2 = 0.931 in atom-based model and Q2 = 0.568, R2 = 0.983 in docking-based model) models own satisfactory performance with good reliabilities and powerful external predictabilities. Molecular docking study suggests that Tyr1230 and Arg1208 might be the key residues, and electrostatic and hydrogen bond interactions were shown to be vital to the activity, concordance with QSAR analysis. Then MD simulation was performed to further explore the binding mode of the most potent inhibitor. The obtained results provide important references for further rational design of c-Met Kinase type I inhibitors.
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25
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Wang KH, Ding DC. Dual targeting of TAM receptors Tyro3, Axl, and MerTK: Role in tumors and the tumor immune microenvironment. Tzu Chi Med J 2020; 33:250-256. [PMID: 34386362 PMCID: PMC8323642 DOI: 10.4103/tcmj.tcmj_129_20] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Revised: 06/12/2020] [Accepted: 07/02/2020] [Indexed: 11/06/2022] Open
Abstract
In both normal and tumor tissues, receptor tyrosine kinases (RTKs) may be pleiotropically expressed. The RTKs not only regulate ordinary cellular processes, including proliferation, survival, adhesion, and migration, but also have a critical role in the development of many types of cancer. The Tyro3, Axl, and MerTK (TAM) family of RTKs (Tyro3, Axl, and MerTK) plays a pleiotropic role in phagocytosis, inflammation, and normal cellular processes. In this article, we highlight the cellular activities of TAM receptors and discuss their roles in cancer and immune cells. We also discuss cancer therapies that target TAM receptors. Further research is needed to elucidate the function of TAM receptors in immune cells toward the development of new targeted immunotherapies for cancer.
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Affiliation(s)
- Kai-Hung Wang
- Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | - Dah-Ching Ding
- Department of Obstetrics and Gynecology, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, Hualien, Taiwan
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26
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Di Stasi R, De Rosa L, D'Andrea LD. Therapeutic aspects of the Axl/Gas6 molecular system. Drug Discov Today 2020; 25:2130-2148. [PMID: 33002607 DOI: 10.1016/j.drudis.2020.09.022] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/14/2020] [Accepted: 09/21/2020] [Indexed: 12/17/2022]
Abstract
Axl receptor tyrosine kinase (RTK) and its ligand, growth arrest-specific protein 6 (Gas6), are involved in several biological functions and participate in the development and progression of a range of malignancies and autoimmune disorders. In this review, we present this molecular system from a drug discovery perspective, highlighting its therapeutic implications and challenges that need to be addressed. We provide an update on Axl/Gas6 axis biology, exploring its role in fields ranging from angiogenesis, cancer development and metastasis, immune response and inflammation to viral infection. Finally, we summarize the molecules that have been developed to date to target the Axl/Gas6 molecular system for therapeutic and diagnostic applications.
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Affiliation(s)
- Rossella Di Stasi
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Napoli, Italy
| | - Lucia De Rosa
- Istituto di Biostrutture e Bioimmagini, CNR, Via Mezzocannone 16, 80134 Napoli, Italy
| | - Luca D D'Andrea
- Istituto di Biostrutture e Bioimmagini, CNR, Via Nizza 52, 10126 Torino, Italy.
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Fujino T, Suda K, Mitsudomi T. Emerging MET tyrosine kinase inhibitors for the treatment of non-small cell lung cancer. Expert Opin Emerg Drugs 2020; 25:229-249. [PMID: 32615820 DOI: 10.1080/14728214.2020.1791821] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Introduction MET aberrations, including MET exon 14 skipping mutation and amplification, are present in ~5% of non-small cell lung cancer (NSCLC) cases, and these levels are comparable to the frequency of ALK fusion. MET amplification also occurs as an acquired resistance mechanism in EGFR-mutated NSCLC after EGFR tyrosine kinase inhibitors (TKI) treatment failure. Therefore, the development of therapies for activated MET is urgently needed. Areas covered This review summarizes (1) the mechanisms and frequencies of MET aberrations in NSCLC, (2) the efficacies and toxicities of MET-TKIs under clinical development and (3) the mechanisms of inherent and acquired resistance to MET-TKIs. Expert opinion Type Ia, Ib and II MET-TKIs are currently under clinical development, and phase I/II studies have shown the potent activities of tepotinib, capmatinib and savolitinib; in fact, tepotinib and capmatinib were approved for use by health authorities. However, inherent and acquired resistance through on- and off-target mechanisms has been detected, and strategies to overcome this resistance are being developed.
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Affiliation(s)
- Toshio Fujino
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
| | - Kenichi Suda
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
| | - Tetsuya Mitsudomi
- Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine , Osaka-Sayama, Japan
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28
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Luo H, Zhang T, Cheng P, Li D, Ogorodniitchouk O, Lahmamssi C, Wang G, Lan M. Therapeutic implications of fibroblast growth factor receptor inhibitors in a combination regimen for solid tumors. Oncol Lett 2020; 20:2525-2536. [PMID: 32782571 DOI: 10.3892/ol.2020.11858] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 05/22/2020] [Indexed: 12/12/2022] Open
Abstract
A number of novel drugs targeting the fibroblast growth factor receptor (FGFR) signaling pathway have been developed, including mostly tyrosine kinase inhibitors, selective inhibitors or monoclonal antibodies. Multiple preclinical and clinical studies have been conducted worldwide to ascertain their effects on diverse solid tumors. Drugs, such as lenvatinib, dovitinib and other non-specific FGFR inhibitors, widely used in clinical practice, have been approved by the Food and Drug Administration for cancer therapy, although the majority of drugs remain in preclinical tests or clinical research. The resistance to a single agent for FGFR inhibition with synthetic lethal action may be overcome by a combination of therapeutic approaches and FGFR inhibitors, which could also enhance the sensitivity to other therapeutics. Therefore, the aim of the present review is to describe the pharmacological characteristics of FGFR inhibitors that may be combined with other therapeutic agents and the preclinical data supporting their combination. Additionally, their clinical implications and the remaining challenges for FGFR inhibitor combination regimens are discussed.
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Affiliation(s)
- Hong Luo
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Tao Zhang
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Peng Cheng
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | - Dong Li
- Department of Oncology, General Hospital of Western Theater Command, Chengdu, Sichuan 610083, P.R. China
| | | | - Chaimaa Lahmamssi
- Institut de Cancérologie Lucien Neuwirth, 42270 Saint Priest en Jarez, France
| | - Ge Wang
- Cancer Center, Institute of Surgical Research, Third Affiliated Hospital, Army Medical University (Third Military Medical University), Chongqing 400042, P.R. China
| | - Meiling Lan
- Cancer Center, The Third Affiliated Hospital of Chongqing Medical University (Jie Er Hospital), Chongqing 401120, P.R. China
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29
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Zhao W, Fan J, Kulic I, Koh C, Clark A, Meuller J, Engkvist O, Barichievy S, Raynoschek C, Hicks R, Maresca M, Wang Q, Brown DG, Lok A, Parro C, Robert J, Chou HY, Zuhl AM, Wood MW, Brandon NJ, Wellington CL. Axl receptor tyrosine kinase is a regulator of apolipoprotein E. Mol Brain 2020; 13:66. [PMID: 32366277 PMCID: PMC7197143 DOI: 10.1186/s13041-020-00609-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2019] [Accepted: 04/24/2020] [Indexed: 12/13/2022] Open
Abstract
Alzheimer's disease (AD), the leading cause of dementia, is a chronic neurodegenerative disease. Apolipoprotein E (apoE), which carries lipids in the brain in the form of lipoproteins, plays an undisputed role in AD pathophysiology. A high-throughput phenotypic screen was conducted using a CCF-STTG1 human astrocytoma cell line to identify small molecules that could upregulate apoE secretion. AZ7235, a previously discovered Axl kinase inhibitor, was identified to have robust apoE activity in brain microglia, astrocytes and pericytes. AZ7235 also increased expression of ATP-binding cassette protein A1 (ABCA1), which is involved in the lipidation and secretion of apoE. Moreover, AZ7235 did not exhibit Liver-X-Receptor (LXR) activity and stimulated apoE and ABCA1 expression in the absence of LXR. Target validation studies using AXL-/- CCF-STTG1 cells showed that Axl is required to mediate AZ7235 upregulation of apoE and ABCA1. Intriguingly, apoE expression and secretion was significantly attenuated in AXL-deficient CCF-STTG1 cells and reconstitution of Axl or kinase-dead Axl significantly restored apoE baseline levels, demonstrating that Axl also plays a role in maintaining apoE homeostasis in astrocytes independent of its kinase activity. Lastly, these effects may require human apoE regulatory sequences, as AZ7235 exhibited little stimulatory activity toward apoE and ABCA1 in primary murine glia derived from neonatal human APOE3 targeted-replacement mice. Collectively, we identified a small molecule that exhibits robust apoE and ABCA1 activity independent of the LXR pathway in human cells and elucidated a novel relationship between Axl and apoE homeostasis in human astrocytes.
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Affiliation(s)
- Wenchen Zhao
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Jianjia Fan
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Iva Kulic
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Cheryl Koh
- Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Boston, USA
| | - Amanda Clark
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Johan Meuller
- Mechanistic Biology & Profiling, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Ola Engkvist
- Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | | | - Carina Raynoschek
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Ryan Hicks
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Marcello Maresca
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Gothenburg, Sweden
| | - Qi Wang
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, USA
| | - Dean G Brown
- Hit Discovery, Discovery Sciences, R&D, AstraZeneca, Boston, USA
| | - Alvin Lok
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Cameron Parro
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Jerome Robert
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Hsien-Ya Chou
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada
| | - Andrea M Zuhl
- Discovery Biology, Discovery Sciences, R&D, AstraZeneca, Boston, USA
| | - Michael W Wood
- Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, USA
| | | | - Cheryl L Wellington
- Department of Pathology and Laboratory Medicine, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, 2215 Wesbrook Mall, Vancouver, British Columbia, V6T 1Z3, Canada.
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Nagamalla L, Kumar JVS. In silico screening of FDA approved drugs on AXL kinase and validation for breast cancer cell line. J Biomol Struct Dyn 2020; 39:2056-2070. [PMID: 32178589 DOI: 10.1080/07391102.2020.1742791] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
AXL kinase has been over expressed in many tumors and its involvement in cell proliferation, migration, survival, and resistance makes the kinase as attractive therapeutic target for many cancers. In this study, we performed a virtual screening of the food and drug administration (FDA) approved drug molecule database against AXL kinase for repurposing studies of breast cancer. We have identified three non-cancer drugs with good binding energies were subjected to in vitro breast cancer MCF-7 cell lines. Three drug molecules showing the activity with good IC50 values toward the cancer cell line. We also carried out a 2 dimensional (2 D) quantitative structure activity relation (QSAR) studies on N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides derivatives to design potent inhibitors for AXL kinase. The final QSAR equation was robust with good predictivity and the statistical validation having R2 and Q2 values are 0.91 and 0.86, respectively. QSAR equation descriptors informs about the chemical properties of AXL inhibitors and helpful for designing novel inhibitors. Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Lavanya Nagamalla
- Department of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, India
| | - J V Shanmukha Kumar
- Department of Chemistry, Koneru Lakshmaiah Education Foundation, Vaddeswaram, India
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31
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Damghani T, Sedghamiz T, Sharifi S, Pirhadi S. Critical c-Met-inhibitor interactions resolved from molecular dynamics simulations of different c-Met complexes. J Mol Struct 2020. [DOI: 10.1016/j.molstruc.2019.127456] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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Haibe Y, Kreidieh M, El Hajj H, Khalifeh I, Mukherji D, Temraz S, Shamseddine A. Resistance Mechanisms to Anti-angiogenic Therapies in Cancer. Front Oncol 2020; 10:221. [PMID: 32175278 PMCID: PMC7056882 DOI: 10.3389/fonc.2020.00221] [Citation(s) in RCA: 250] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 02/10/2020] [Indexed: 12/12/2022] Open
Abstract
Tumor growth and metastasis rely on tumor vascular network for the adequate supply of oxygen and nutrients. Tumor angiogenesis relies on a highly complex program of growth factor signaling, endothelial cell (EC) proliferation, extracellular matrix (ECM) remodeling, and stromal cell interactions. Numerous pro-angiogenic drivers have been identified, the most important of which is the vascular endothelial growth factor (VEGF). The importance of pro-angiogenic inducers in tumor growth, invasion and extravasation make them an excellent therapeutic target in several types of cancers. Hence, the number of anti-angiogenic agents developed for cancer treatment has risen over the past decade, with at least eighty drugs being investigated in preclinical studies and phase I-III clinical trials. To date, the most common approaches to the inhibition of the VEGF axis include the blockade of VEGF receptors (VEGFRs) or ligands by neutralizing antibodies, as well as the inhibition of receptor tyrosine kinase (RTK) enzymes. Despite promising preclinical results, anti-angiogenic monotherapies led only to mild clinical benefits. The minimal benefits could be secondary to primary or acquired resistance, through the activation of alternative mechanisms that sustain tumor vascularization and growth. Mechanisms of resistance are categorized into VEGF-dependent alterations, non-VEGF pathways and stromal cell interactions. Thus, complementary approaches such as the combination of these inhibitors with agents targeting alternative mechanisms of blood vessel formation are urgently needed. This review provides an updated overview on the pathophysiology of angiogenesis during tumor growth. It also sheds light on the different pro-angiogenic and anti-angiogenic agents that have been developed to date. Finally, it highlights the preclinical evidence for mechanisms of angiogenic resistance and suggests novel therapeutic approaches that might be exploited with the ultimate aim of overcoming resistance and improving clinical outcomes for patients with cancer.
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Affiliation(s)
- Yolla Haibe
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Malek Kreidieh
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Hiba El Hajj
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
- Department of Experimental Pathology, Immunology and Microbiology, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ibrahim Khalifeh
- Department of Pathology and Laboratory Medicine, American University of Beirut Medical Center, Beirut, Lebanon
| | - Deborah Mukherji
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Sally Temraz
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
| | - Ali Shamseddine
- Division of Hematology/Oncology, Department of Internal Medicine, American University of Beirut-Medical Center, Beirut, Lebanon
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Ramezani S, Vousooghi N, Joghataei MT, Chabok SY. The Role of Kinase Signaling in Resistance to Bevacizumab Therapy for Glioblastoma Multiforme. Cancer Biother Radiopharm 2020; 34:345-354. [PMID: 31411929 DOI: 10.1089/cbr.2018.2651] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Glioblastoma multiforme (GBM) is the most malignant primary brain tumor and is characterized by vascular hyperplasia, necrosis, and high cell proliferation. Despite current standard therapies, including surgical resection and chemoradiotherapy, GBM patients survive for only about 15 months after diagnosis. Recently, the U.S. Food and Drug Administration (FDA) has approved an antiangiogenesis medication for recurrent GBM-bevacizumab-which has improved progression-free survival in GBM patients. Although bevacizumab has resulted in significant early clinical benefit, it inescapably predisposes tumor to relapse that can be represented as an infiltrative phenotype. Fundamentally, bevacizumab antagonizes the vascular endothelial growth factor A (VEGFA), which is consistently released on both endothelial cells (ECs) and GBM cells. Actually, VEGFA inhibition on the ECs leads to the suppression of vascular progression, permeability, and the vasogenic edema. However, the consequence of the VEGFA pathway blockage on the GBM cells remains controversial. Nevertheless, a piece of evidence supports the relationship between bevacizumab application and compensatory activation of kinase signaling within GBM cells, leading to a tumor cell invasion known as the main mechanism of bevacizumab-induced tumor resistance. A complete understanding of kinase responses associated with tumor invasion in bevacizumab-resistant GBMs offers new therapeutic opportunities. Thus, this study aimed at presenting a brief overview of preclinical and clinical data of the tumor invasion and resistance induced by bevacizumab administration in GBMs, with a focus on the kinase responses during treatment. The novel therapeutic strategies to overcome this resistance by targeting protein kinases have also been summarized.
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Affiliation(s)
- Sara Ramezani
- 1Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,2Guilan Road Trauma Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Nasim Vousooghi
- 3Department of Neuroscience, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran.,4Iranian National Center for Addiction Studies (INCAS), Tehran University of Medical Sciences, Tehran, Iran.,5Research Center for Cognitive and Behavioral Sciences, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohammad Taghi Joghataei
- 6Department of Neuroscience, School of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.,7Cellular and Molecular Research Center, Iran University of Medical Sciences, Tehran, Iran
| | - Shahrokh Yousefzadeh Chabok
- 1Neuroscience Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.,2Guilan Road Trauma Research Center, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
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Ghosh Roy S. TAM receptors: A phosphatidylserine receptor family and its implications in viral infections. TAM RECEPTORS IN HEALTH AND DISEASE 2020; 357:81-122. [DOI: 10.1016/bs.ircmb.2020.09.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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AXL receptor tyrosine kinase as a promising anti-cancer approach: functions, molecular mechanisms and clinical applications. Mol Cancer 2019; 18:153. [PMID: 31684958 PMCID: PMC6827209 DOI: 10.1186/s12943-019-1090-3] [Citation(s) in RCA: 336] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Accepted: 10/18/2019] [Indexed: 02/08/2023] Open
Abstract
Molecular targeted therapy for cancer has been a research hotspot for decades. AXL is a member of the TAM family with the high-affinity ligand growth arrest-specific protein 6 (GAS6). The Gas6/AXL signalling pathway is associated with tumour cell growth, metastasis, invasion, epithelial-mesenchymal transition (EMT), angiogenesis, drug resistance, immune regulation and stem cell maintenance. Different therapeutic agents targeting AXL have been developed, typically including small molecule inhibitors, monoclonal antibodies (mAbs), nucleotide aptamers, soluble receptors, and several natural compounds. In this review, we first provide a comprehensive discussion of the structure, function, regulation, and signalling pathways of AXL. Then, we highlight recent strategies for targeting AXL in the treatment of cancer.AXL-targeted drugs, either as single agents or in combination with conventional chemotherapy or other small molecule inhibitors, are likely to improve the survival of many patients. However, future investigations into AXL molecular signalling networks and robust predictive biomarkers are warranted to select patients who could receive clinical benefit and to avoid potential toxicities.
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Sun ZG, Liu JH, Zhang JM, Qian Y. Research Progress of Axl Inhibitors. Curr Top Med Chem 2019; 19:1338-1349. [PMID: 31218961 DOI: 10.2174/1568026619666190620155613] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 04/24/2019] [Accepted: 04/30/2019] [Indexed: 02/07/2023]
Abstract
Axl, a Receptor Tyrosine Kinase (RTK) belonging to the TAM (Axl, Mer, Tyro3) family, participates in many signal transduction cascades after mostly being stimulated by Growth arrestspecific 6(Gas6). Axl is widely expressed in many organs, such as macrophages, endothelial cells, heart, liver and skeletal muscle. Over-expression and activation of Axl are associated with promoting chemotherapy resistance, cell proliferation, invasion and metastasis in many human cancers, such as breast, lung, and pancreatic cancers. Therefore, the research and development of Axl inhibitors is of great significance to strengthen the means of cancer treatment, especially to solve the problem of drug resistance. Axl inhibitors have attracted more and more researchers' attention in recent years. This review discusses the research progress of Axl inhibitors in recent years.
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Affiliation(s)
- Zhi-Gang Sun
- Central Laboratory, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400, China.,State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, No.163 Xianlin Road, Nanjing 210023, China
| | - Jian-Hua Liu
- Central Laboratory, Linyi Central Hospital, No.17 Jiankang Road, Linyi 276400, China
| | - Jin-Mai Zhang
- Room 205, BIO-X white house, Shanghai Jiao Tong University, No.1954 Huashan Road, Shanghai 200030, China
| | - Yong Qian
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, No.163 Xianlin Road, Nanjing 210023, China
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Zhang J, Tang PMK, Zhou Y, Cheng ASL, Yu J, Kang W, To KF. Targeting the Oncogenic FGF-FGFR Axis in Gastric Carcinogenesis. Cells 2019; 8:cells8060637. [PMID: 31242658 PMCID: PMC6627225 DOI: 10.3390/cells8060637] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2019] [Revised: 06/14/2019] [Accepted: 06/24/2019] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer (GC) is one of the most wide-spread malignancies in the world. The oncogenic role of signaling of fibroblast growing factors (FGFs) and their receptors (FGFRs) in gastric tumorigenesis has been gradually elucidated by recent studies. The expression pattern and clinical correlations of FGF and FGFR family members have been comprehensively delineated. Among them, FGF18 and FGFR2 demonstrate the most prominent driving role in gastric tumorigenesis with gene amplification or somatic mutations and serve as prognostic biomarkers. FGF-FGFR promotes tumor progression by crosstalking with multiple oncogenic pathways and this provides a rational therapeutic strategy by co-targeting the crosstalks to achieve synergistic effects. In this review, we comprehensively summarize the pathogenic mechanisms of FGF-FGFR signaling in gastric adenocarcinoma together with the current targeted strategies in aberrant FGF-FGFR activated GC cases.
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Affiliation(s)
- Jinglin Zhang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
| | - Patrick M K Tang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
| | - Yuhang Zhou
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
| | - Alfred S L Cheng
- School of Biomedical Sciences, The Chinese University of Hong Kong, Hong Kong, China.
| | - Jun Yu
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.
| | - Wei Kang
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
| | - Ka Fai To
- Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, China.
- Institute of Digestive Disease, State Key Laboratory of Digestive Disease, The Chinese University of Hong Kong, Hong Kong, China.
- Li Ka Shing Institute of Health Science, Sir Y.K. Pao Cancer Center, The Chinese University of Hong Kong, Hong Kong, China.
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AURKB as a target in non-small cell lung cancer with acquired resistance to anti-EGFR therapy. Nat Commun 2019; 10:1812. [PMID: 31000705 PMCID: PMC6472415 DOI: 10.1038/s41467-019-09734-5] [Citation(s) in RCA: 91] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2018] [Accepted: 03/28/2019] [Indexed: 01/19/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) tumors harboring mutations in EGFR ultimately relapse to therapy with EGFR tyrosine kinase inhibitors (EGFR TKIs). Here, we show that resistant cells without the p.T790M or other acquired mutations are sensitive to the Aurora B (AURKB) inhibitors barasertib and S49076. Phospho-histone H3 (pH3), a major product of AURKB, is increased in most resistant cells and treatment with AURKB inhibitors reduces the levels of pH3, triggering G1/S arrest and polyploidy. Senescence is subsequently induced in cells with acquired mutations while, in their absence, polyploidy is followed by cell death. Finally, in NSCLC patients, pH3 levels are increased after progression on EGFR TKIs and high pH3 baseline correlates with shorter survival. Our results reveal that AURKB activation is associated with acquired resistance to EGFR TKIs, and that AURKB constitutes a potential target in NSCLC progressing to anti-EGFR therapy and not carrying resistance mutations. Non-small cell lung cancer with EGFR mutations are known to develop resistance to EGFR tyrosine kinase inhibitors. Here, the authors show AURKB activation to be associated with resistance in EGFR mutant lung cancer cells, and that AURKB is a therapeutic target in resistant tumours that lack the p.T790M or other acquired mutations.
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Jiang W, Ji M. Receptor tyrosine kinases in PI3K signaling: The therapeutic targets in cancer. Semin Cancer Biol 2019; 59:3-22. [PMID: 30943434 DOI: 10.1016/j.semcancer.2019.03.006] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2018] [Revised: 03/09/2019] [Accepted: 03/28/2019] [Indexed: 12/17/2022]
Abstract
The phosphoinositide 3-kinase (PI3K) pathway, one of the most commonly activated signaling pathways in human cancers, plays a crucial role in the regulation of cell proliferation, differentiation, and survival. This pathway is usually activated by receptor tyrosine kinases (RTKs), whose constitutive and aberrant activation is via gain-of-function mutations, chromosomal rearrangement, gene amplification and autocrine. Blockage of PI3K pathway by targeted therapy on RTKs with tyrosine kinases inhibitors (TKIs) and monoclonal antibodies (mAbs) has achieved great progress in past decades; however, there still remain big challenges during their clinical application. In this review, we provide an overview about the most frequently encountered alterations in RTKs and focus on current therapeutic agents developed to counteract their aberrant functions, accompanied with discussions of two major challenges to the RTKs-targeted therapy in cancer - resistance and toxicity.
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Affiliation(s)
- Wei Jiang
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China
| | - Meiju Ji
- Key Laboratory for Tumor Precision Medicine of Shaanxi Province, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China; Center for Translational Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, PR China.
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Wang Y, Xing L, Ji Y, Ye J, Dai Y, Gu W, Ai J, Song Z. Discovery of a potent tyrosine kinase AXL inhibitor bearing the 3-((2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl)amino)pyrazine core. Bioorg Med Chem Lett 2019; 29:836-838. [PMID: 30685094 DOI: 10.1016/j.bmcl.2019.01.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 01/15/2019] [Accepted: 01/16/2019] [Indexed: 11/24/2022]
Abstract
Starting from the recently launched FLT3/AXL multi-targeted inhibitor Gilteritinib (5), we conducted a side-chain ring closure medicinal chemistry approach leading to the identification of compound 15c as a highly potent AXL inhibitor in the biochemical and cellular anti-proliferative assays, with IC50 values of 1.2 and 0.3 nM, respectively. Compared with the reference compound 5, our new discovered AXL inhibitor 15c is more potent in both assays.
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Affiliation(s)
- Yueliang Wang
- Shanghai Key Laboratory of Bio-Energy Crops, School of Life Sciences, Shanghai University, Shanghai 200444, China; Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Li Xing
- CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Yinchun Ji
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Jiqing Ye
- CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Yang Dai
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Wangting Gu
- CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China
| | - Jing Ai
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
| | - Zilan Song
- CAS Key Laboratory of Receptor Research and the State Key Laboratory for Drug Research, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai 201203, China; University of Chinese Academy of Sciences, Beijing 100049, China.
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Sun ZG, Yang YA, Zhang ZG, Zhu HL. Optimization techniques for novel c-Met kinase inhibitors. Expert Opin Drug Discov 2018; 14:59-69. [PMID: 30518273 DOI: 10.1080/17460441.2019.1551355] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Zhi-Gang Sun
- Central Laboratory, Linyi Central Hospital, Linyi, China
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Yong-An Yang
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
| | - Zhi-Gang Zhang
- Department of Cardiology, Linyi Central Hospital, Linyi, China
| | - Hai-Liang Zhu
- State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China
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Du W, Brekken RA. Does Axl have potential as a therapeutic target in pancreatic cancer? Expert Opin Ther Targets 2018; 22:955-966. [PMID: 30244621 PMCID: PMC6292430 DOI: 10.1080/14728222.2018.1527315] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Pancreatic cancer is a leading cause of cancer-related death. Metastasis, therapy resistance, and immunosuppression are dominant characteristics of pancreatic tumors. Strategies that enhance the efficacy of standard of care and/or immune therapy are likely the most efficient route to improve overall survival in this disease. Areas covered: Axl, a member of the TAM (Tyro3, Axl, MerTK) family of receptor tyrosine kinases, is involved in cell plasticity, chemoresistance, immune suppression, and metastasis in various cancers, including pancreatic cancer. This review provides an overview of Axl and its function in normal conditions, summarizes the regulation and function of Axl in cancer, and highlights the contribution of Axl to pancreatic cancer as well as its potential as a therapeutic target. Expert opinion: Axl is an attractive therapeutic target in pancreatic cancer because it contributes to many of the roadblocks that hamper therapeutic efficacy. Clinical evidence supporting Axl inhibition in pancreatic cancer is currently limited; however, multiple clinical trials have been initiated or are in the planning phase to test the effect of inhibiting Axl in conjunction with standard therapy in pancreatic cancer patients. We anticipate that these studies will provide robust validation of Axl as a therapeutic target in pancreatic cancer.
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43
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Katoh M. Fibroblast growth factor receptors as treatment targets in clinical oncology. Nat Rev Clin Oncol 2018; 16:105-122. [DOI: 10.1038/s41571-018-0115-y] [Citation(s) in RCA: 254] [Impact Index Per Article: 36.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Tang Q, Duan Y, Xiong H, Chen T, Xiao Z, Wang L, Xiao Y, Huang S, Xiong Y, Zhu W, Gong P, Zheng P. Synthesis and antiproliferative activity of 6,7-disubstituted-4-phenoxyquinoline derivatives bearing the 1,8-naphthyridin-2-one moiety. Eur J Med Chem 2018; 158:201-213. [DOI: 10.1016/j.ejmech.2018.08.066] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 08/23/2018] [Accepted: 08/24/2018] [Indexed: 12/18/2022]
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Szabadkai I, Torka R, Garamvölgyi R, Baska F, Gyulavári P, Boros S, Illyés E, Choidas A, Ullrich A, Őrfi L. Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors. J Med Chem 2018; 61:6277-6292. [PMID: 29928803 DOI: 10.1021/acs.jmedchem.8b00672] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
The overexpression of AXL kinase has been described in many types of cancer. Due to its role in proliferation, survival, migration, and resistance, AXL represents a promising target in the treatment of the disease. In this study we present a novel compound family that successfully targets the AXL kinase. Through optimization and detailed SAR studies we developed low nanomolar inhibitors, and after further biological characterization we identified a potent AXL kinase inhibitor with favorable pharmacokinetic profile. The antitumor activity was determined in xenograft models, and the lead compounds reduced the tumor size by 40% with no observed toxicity as well as lung metastasis formation by 66% when compared to vehicle control.
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Affiliation(s)
| | - Robert Torka
- Institute of Physiological Chemistry , University Halle-Wittenberg , Halle (Saale) 06108 , Germany
| | - Rita Garamvölgyi
- Vichem Chemie Research Ltd. , Budapest 1022 , Hungary
- Department of Pharmaceutical Chemistry , Semmelweis University , Budapest 1092 , Hungary
| | - Ferenc Baska
- Vichem Chemie Research Ltd. , Budapest 1022 , Hungary
| | - Pál Gyulavári
- Department of Medical Chemistry, Molecular Biology and Pathobiochemistry , Semmelweis University , Budapest 1094 , Hungary
| | - Sándor Boros
- Vichem Chemie Research Ltd. , Budapest 1022 , Hungary
| | - Eszter Illyés
- Vichem Chemie Research Ltd. , Budapest 1022 , Hungary
| | - Axel Choidas
- Lead Discovery Center GmbH , Dortmund 44227 , Germany
| | - Axel Ullrich
- Department of Molecular Biology , Max Planck Institute of Biochemistry , Martinsried 82152 , Germany
| | - László Őrfi
- Vichem Chemie Research Ltd. , Budapest 1022 , Hungary
- Department of Pharmaceutical Chemistry , Semmelweis University , Budapest 1092 , Hungary
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Itatani Y, Kawada K, Yamamoto T, Sakai Y. Resistance to Anti-Angiogenic Therapy in Cancer-Alterations to Anti-VEGF Pathway. Int J Mol Sci 2018; 19:ijms19041232. [PMID: 29670046 PMCID: PMC5979390 DOI: 10.3390/ijms19041232] [Citation(s) in RCA: 245] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2018] [Revised: 04/12/2018] [Accepted: 04/15/2018] [Indexed: 02/06/2023] Open
Abstract
Anti-angiogenic therapy is one of the promising strategies for many types of solid cancers. Bevacizumab (Avastin), a recombinant humanized monoclonal antibody of vascular endothelial growth factor (VEGF) A, was approved for the first time as an anti-angiogenic drug for the treatment of metastatic colorectal cancer (CRC) by the Food and Drug Administration (FDA) in 2004. In addition, the other VEGF pathway inhibitors including small molecule tyrosine kinase inhibitors (sunitinib, sorafenib, and pazopanib), a soluble VEGF decoy receptor (aflibercept), and a humanized monoclonal antibody of VEGF receptor 2 (VEGFR2) (ramucirumab) have been approved for cancer therapy. Although many types of VEGF pathway inhibitors can improve survival in most cancer patients, some patients have little or no beneficial effect from them. The primary or acquired resistance towards many oncological drugs, including anti-VEGF inhibitors, is a common problem in cancer treatment. This review summarizes the proposed alternative mechanisms of angiogenesis other than the VEGF pathway. These mechanisms are involved in the development of resistance to anti-VEGF therapies in cancer patients.
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Affiliation(s)
- Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Takamasa Yamamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
- Moores Cancer Center, University of California San Diego, San Diego, CA 92093, USA.
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
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Shen Y, Chen X, He J, Liao D, Zu X. Axl inhibitors as novel cancer therapeutic agents. Life Sci 2018; 198:99-111. [PMID: 29496493 DOI: 10.1016/j.lfs.2018.02.033] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2017] [Revised: 02/07/2018] [Accepted: 02/23/2018] [Indexed: 12/17/2022]
Abstract
Overexpression and activation of Axl receptor tyrosine kinase have been widely accepted to promote cell proliferation, chemotherapy resistance, invasion, and metastasis in several human cancers, such as lung, breast, and pancreatic cancers. Axl, a member of the TAM (Tyro3, Axl, Mer) family, and its inhibitors can specifically break the kinase signaling nodes, allowing advanced patients to regain drug sensitivity with improved therapeutic efficacy. Therefore, the research on Axl is promising and it is worthy of further investigations. In this review, we present an update on the Axl inhibitors and provide new insights into their latent application.
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Affiliation(s)
- Yingying Shen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Xiguang Chen
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Jun He
- Department of Spine Surgery, the Affiliated Nanhua Hospital of University of South China, Hengyang, Hunan 421001, PR China
| | - Duanfang Liao
- Division of Stem Cell Regulation and Application, Key Laboratory for Quality Evaluation of Bulk Herbs of Hunan Province, Hunan University of Chinese Medicine, Changsha 410208, Hunan, PR China
| | - Xuyu Zu
- Institute of Clinical Medicine, The First Affiliated Hospital of University of South China, Hengyang, Hunan 421001, PR China.
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Parikh PK, Ghate MD. Recent advances in the discovery of small molecule c-Met Kinase inhibitors. Eur J Med Chem 2018; 143:1103-1138. [DOI: 10.1016/j.ejmech.2017.08.044] [Citation(s) in RCA: 111] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2017] [Revised: 08/03/2017] [Accepted: 08/21/2017] [Indexed: 12/17/2022]
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Abstract
A major challenge in anticancer treatment is the pre-existence or emergence of resistance to therapy. AXL and MER are two members of the TAM (TYRO3-AXL-MER) family of receptor tyrosine kinases, which, when activated, can regulate tumor cell survival, proliferation, migration and invasion, angiogenesis, and tumor-host interactions. An increasing body of evidence strongly suggests that these receptors play major roles in resistance to targeted therapies and conventional cytotoxic agents. Multiple resistance mechanisms exist, including the direct and indirect crosstalk of AXL and MER with other receptors and the activation of feedback loops regulating AXL and MER expression and activity. These mechanisms may be innate, adaptive, or acquired. A principal role of AXL appears to be in sustaining a mesenchymal phenotype, itself a major mechanism of resistance to diverse anticancer therapies. Both AXL and MER play a role in the repression of the innate immune response which may also limit response to treatment. Small molecule and antibody inhibitors of AXL and MER have recently been described, and some of these have already entered clinical trials. The optimal design of treatment strategies to maximize the clinical benefit of these AXL and MER targeting agents are discussed in relation to the different cancer types and the types of resistance encountered. One of the major challenges to successful development of these therapies will be the application of robust predictive biomarkers for clear-cut patient stratification.
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Rodon J, Postel-Vinay S, Hollebecque A, Nuciforo P, Azaro A, Cattan V, Marfai L, Sudey I, Brendel K, Delmas A, Malasse S, Soria JC. First-in-human phase I study of oral S49076, a unique MET/AXL/FGFR inhibitor, in advanced solid tumours. Eur J Cancer 2017. [PMID: 28624695 DOI: 10.1016/j.ejca.2017.05.007] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
BACKGROUND AND OBJECTIVES S49076 is a novel ATP-competitive tyrosine kinase inhibitor of MET, AXL and FGFR with a unique selectivity profile. A phase I open-label study was undertaken to establish the tolerability profile and determine the recommended dose (RD) and administration schedule. MATERIALS AND METHODS Patients with advanced solid tumours received S49076 orally once-daily (qd) or twice-daily (bid) in continuous 21-day cycles at escalating doses guided by a 3 + 3 design and followed by an expansion phase at the RD. Pharmacokinetic (PK) parameters were assessed and pharmacodynamic end-points were evaluated in pre- and post-treatment tumour biopsies. Preliminary anti-tumour activity was evaluated as per the Response Evaluation Criteria In Solid Tumours 1.1 criteria. RESULTS A total of 103 patients were treated: 79 in the dose-escalation and 24 in the expansion. Doses from 15 to 900 mg were evaluated. Dose-limiting toxicities were reported in 9 patients and occurred at 30, 760 and 900 mg in the qd arm and at 180, 225 and 285 mg in the bid arm. The RD was defined at 600 mg qd. Adverse events (AEs) occurred with similar frequency in both regimens at an equivalent total daily dose. Overall, 83 patients (81.4%) had drug-related AEs, the majority (93%) of which were grade I-II (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0) and only 3% led to drug discontinuation. Intratumoural PK analysis at the RD suggested hitting of MET, AXL and FGFR. CONCLUSION S49076 demonstrated a tolerable safety profile with limited single-agent activity. PK/pharmacodynamic readouts of S49076 are encouraging for further investigation of S49076 in combination therapies. TRIAL REGISTRATION NUMBER ISRCTN00759419.
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Affiliation(s)
- Jordi Rodon
- Medical Oncology, Vall D'Hebron University Hospital and Vall D'Hebron Institut D'Oncologia, Barcelona, Spain.
| | - Sophie Postel-Vinay
- Drug Development Department DITEP, Institut Gustave Roussy, 94805, Villejuif, France; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Orsay, 91405, France
| | - Antoine Hollebecque
- Drug Development Department DITEP, Institut Gustave Roussy, 94805, Villejuif, France; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Orsay, 91405, France
| | - Paolo Nuciforo
- Molecular Oncology Laboratory, Vall D'Hebron University Hospital Institut D'Oncologia, Barcelona, Spain
| | - Analia Azaro
- Medical Oncology, Vall D'Hebron University Hospital and Vall D'Hebron Institut D'Oncologia, Barcelona, Spain
| | - Valérie Cattan
- Oncology R&D Unit, Institut de Recherches Internationales Servier, 92284, Suresnes, France
| | - Lucie Marfai
- Oncology R&D Unit, Institut de Recherches Internationales Servier, 92284, Suresnes, France
| | - Isabelle Sudey
- Oncology R&D Unit, Institut de Recherches Internationales Servier, 92284, Suresnes, France
| | - Karl Brendel
- Division of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, 92284, Suresnes, France
| | - Audrey Delmas
- Division of Clinical Pharmacokinetics and Pharmacometrics, Institut de Recherches Internationales Servier, 92284, Suresnes, France
| | - Stéphanie Malasse
- Division of Biostatistics, Institut de Recherches Internationales Servier, 92284, Suresnes, France
| | - Jean-Charles Soria
- Drug Development Department DITEP, Institut Gustave Roussy, 94805, Villejuif, France; Université Paris-Sud, Faculté de Médecine, Université Paris-Saclay, Orsay, 91405, France
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