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Balaji SK, Balasundarasekar B, Khuwaja WM, Dolan KM, Dong X. Antimicrobial Peptide Signaling in Skin Diseases. JID INNOVATIONS 2025; 5:100354. [PMID: 40104692 PMCID: PMC11914806 DOI: 10.1016/j.xjidi.2025.100354] [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: 07/30/2024] [Revised: 01/03/2025] [Accepted: 01/21/2025] [Indexed: 03/20/2025] Open
Abstract
Antimicrobial peptides (AMPs) are important innate immune molecules at microbe-host interfaces. The biophysical properties of AMPs that facilitate direct killing of microbes have been extensively reviewed. In this article, we focus on how AMPs perform immunomodulatory functions through interaction with host receptors on epithelial, immune, and neuronal cell types. We summarize the current knowledge of known AMPs in the skin, the receptors that respond to AMPs, and the downstream intracellular signaling pathways. In the end, we discuss the roles of AMP signaling systems in skin diseases.
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Affiliation(s)
- Sharan Kumar Balaji
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA
| | | | - Waris Muhammad Khuwaja
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA
| | - Keean Michael Dolan
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA
| | - Xintong Dong
- Department of Biological Sciences, The University of Texas at Dallas, Richardson, Texas, USA
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2
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Zhang M, Fu Y, Xie T, Yang Z, Zhang D, Zhou R. Physical insights guided rational design of anti-EGFR antibody to reverse the acquired resistance. Int J Biol Macromol 2025:141304. [PMID: 39986495 DOI: 10.1016/j.ijbiomac.2025.141304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 01/24/2025] [Accepted: 02/18/2025] [Indexed: 02/24/2025]
Abstract
Cetuximab (Ctx), a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) for colorectal cancer treatment, often faces diminished clinical efficacy due to acquired resistance driven by EGFR mutations. Here, we investigated the molecular mechanisms underlying this mutation-induced drug resistance and developed a mechanism-based strategy to restore the binding affinity of Ctx to EGFR mutants. Through molecular dynamics simulations and free energy perturbation calculations, we discovered that most resistant mutations primarily alter the electrostatic properties of the binding interface. Focusing on two key mutations, EGFR K489E and I491M, we rationally designed two Ctx variants-CtxD103R for EGFRK489E and CtxD103E_E105D for EGFRI491M-using electrostatic compensation and steric hindrance adjustment strategies. Surface plasmon resonance measurements verified that the two designed Ctx variants exhibit improved binding affinity to the corresponding EGFR mutants compared with wild-type Ctx. Additionally, western blot experiments using HEK-293 T cells showed that the designed CtxD103R effectively inhibits EGF-stimulated phosphorylation of EGFRK489E. Our findings highlight a rational design approach, empowered by interaction landscape at atomic detail, as a promising and cost-effective strategy to combat mutation-driven resistance in antibody therapies.
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Affiliation(s)
- Mingjiao Zhang
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Yaqi Fu
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Teng Xie
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Zaixing Yang
- State Key Laboratory of Radiation Medicine and Protection, School for Radiological and Interdisciplinary Sciences (RAD-X), Soochow University, Suzhou 215123, China
| | - Dong Zhang
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China
| | - Ruhong Zhou
- School of Physics, Institute of Quantitative Biology, and College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang 310058, China; The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang 310058, China; Department of Chemistry, Columbia University, New York, NY 10027, United States.
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3
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Liao Z, Luo C, Huang Y, Jiang Z, Wei H, Wang Y. Evaluation of the safety profile of amivantamab based on real-world evidence: a call to vigilance. Expert Opin Drug Saf 2025:1-10. [PMID: 39829078 DOI: 10.1080/14740338.2025.2456167] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2024] [Accepted: 11/18/2024] [Indexed: 01/22/2025]
Abstract
BACKGROUND Amivantamab has been approved for EGFR exon 20 insertion-mutated non-small-cell lung cancer. The aim of this study was to perform an in-depth analysis of its safety profile. RESEARCH DESIGN AND METHODS Safety reports were collected from the database of the Food and Drug Administration Adverse Event Reporting System from April 2021 to September 2023, and the reporting odds ratio (ROR) method was used to detect potential safety signals. Mobocertinib, an agent with similar properties to amivantamab, served as a control for comparison. RESULTS A total of 88 safety signals were detected, most of which were novel. In comparison with mobocertinib, amivantamab appeared to cause more injury, poisoning, and procedural complications (ROR = 15.54, 95% CI 10.25-23.58); respiratory, thoracic, and mediastinal disorders (ROR = 1.92, 95% CI 1.57-2.34); infections and infestations (ROR = 1.39, 95% CI 1.09-1.76); blood and lymphatic system disorders (ROR = 9.57, 95% CI 6.17-14.84); and immune system disorders (ROR = 6.41, 95% CI 3.14-13.12). Moreover, amivantamab was associated with higher risks of thrombosis events, bone marrow suppression, skin and soft tissue infection, deterioration of respiratory symptoms, and noninfectious pneumonitis. CONCLUSION The safety profile of amivantamab requires attention; particularly, monitoring of the adverse drug events described above is necessary during its administration.
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Affiliation(s)
- Zuyue Liao
- Department of Pharmacy, Mianyang Hospital of Traditional Chinese Medicine, Mianyang Hospital of Chengdu University of Traditional Chinese Medicine, Mianyang, Sichuan, China
| | - Cheng Luo
- Department of Pharmacy, Mianyang Hospital of Traditional Chinese Medicine, Mianyang Hospital of Chengdu University of Traditional Chinese Medicine, Mianyang, Sichuan, China
| | - Yinghua Huang
- Center for Preventive Treatment of Diseases, Mianyang Hospital of Traditional Chinese Medicine, Mianyang Hospital of Chengdu University of Traditional Chinese Medicine, Mianyang, Sichuan, China
| | - Zhongcai Jiang
- Department of Pharmacy, Mianyang Hospital of Traditional Chinese Medicine, Mianyang Hospital of Chengdu University of Traditional Chinese Medicine, Mianyang, Sichuan, China
| | - Hongqun Wei
- Department of Pharmacy, Mianyang Hospital of Traditional Chinese Medicine, Mianyang Hospital of Chengdu University of Traditional Chinese Medicine, Mianyang, Sichuan, China
| | - Yu Wang
- Department of Pharmacy, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, Sichuan, China
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Su Q, Chen J, Liu Z, Fan Y, He S. A pH-Sensitive cRGD-PEG-siRNA Conjugated Compound Targeting Glioblastoma. Bioconjug Chem 2024; 35:1732-1743. [PMID: 39431993 PMCID: PMC11583972 DOI: 10.1021/acs.bioconjchem.4c00255] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
Glioblastoma ranks among the most prevalent primary intracranial tumors, characterized by high mortality and poor prognosis. Chemotherapy remains a key treatment strategy for gliomas, though most current drugs suffer from limited efficacy and significant toxicity. This study focuses on a cRGD-siEGFR coupling compound synthesized in a previous stage. Prior research indicated that cRGD-siEGFR molecules exhibited certain targeting and antitumor properties but faced issues of inadequate targeting, low efficacy, and high renal toxicity. To enhance antitumor efficacy and mitigate side effects, a pH-responsive, long-circulating, and highly targeted siRNA delivery system, the cRGD-PEG-siEGFR conjugate, was developed. The targeting, antitumor effects, and biological distribution of cRGD-PEG-siEGFR were examined. The results demonstrated that cRGD-PEG-siEGFR was effectively taken up by αvβ3-positive U87MG cells, specifically silenced EGFR gene expression, and exhibited antitumor effects. In normal physiological conditions, it avoided uptake by normal cells, thereby reducing side effects. Furthermore, in vivo biodistribution experiments revealed that cRGD-PEG-siEGFR, compared to cRGD-siEGFR, significantly decreased renal accumulation and exhibited prolonged circulation. Consequently, cRGD-PEG-siRNA emerges as a promising drug candidate with attributes of long circulation, high targeting, pH responsiveness, and substantial antitumor efficacy.
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Affiliation(s)
- Qing Su
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China
| | - Junxiao Chen
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China
| | - Ziyuan Liu
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China
| | - Yiqi Fan
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China
| | - Shuai He
- Department of Pharmacy, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510655, China
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5
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Zasheva D, Mladenov P, Zapryanova S, Gospodinova Z, Georgieva M, Alexandar I, Velinov V, Djilianov D, Moyankova D, Simova-Stoilova L. Cytotoxic Effects of Plant Secondary Metabolites and Naturally Occurring Bioactive Peptides on Breast Cancer Model Systems: Molecular Mechanisms. Molecules 2024; 29:5275. [PMID: 39598664 PMCID: PMC11596968 DOI: 10.3390/molecules29225275] [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: 09/30/2024] [Revised: 10/30/2024] [Accepted: 11/06/2024] [Indexed: 11/29/2024] Open
Abstract
Breast cancer is the second leading cause of death among women, and the number of mortal cases in diagnosed patients is constantly increasing. The search for new plant compounds with antitumor effects is very important because of the side effects of conventional therapy and the development of drug resistance in cancer cells. The use of plant substances in medicine has been well known for centuries, but the exact mechanism of their action is far from being elucidated. The molecular mechanisms of cytotoxicity exerted by secondary metabolites and bioactive peptides of plant origin on breast cancer cell lines are the subject of this review.
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Affiliation(s)
- Diana Zasheva
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tsarigradsko Shosse, 73, 1113 Sofia, Bulgaria; (D.Z.); (S.Z.)
| | - Petko Mladenov
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Silvina Zapryanova
- Institute of Biology and Immunology of Reproduction, Bulgarian Academy of Sciences, Tsarigradsko Shosse, 73, 1113 Sofia, Bulgaria; (D.Z.); (S.Z.)
| | - Zlatina Gospodinova
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Mariyana Georgieva
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Irina Alexandar
- Institute of Molecular Biology “Rumen Tzanev”, Bulgarian Academy of Sciences, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria;
| | - Valentin Velinov
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
| | - Dimitar Djilianov
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Daniela Moyankova
- Agrobioinstitute, Agricultural Academy, bul. “Dragan Tsankov” 8, 1164 Sofia, Bulgaria; (P.M.); (D.D.); (D.M.)
| | - Lyudmila Simova-Stoilova
- Institute of Plant Physiology and Genetics, Bulgarian Academy of Science, “Acad. Georgi Bonchev” Str., Bl. 21, 1113 Sofia, Bulgaria; (Z.G.); (M.G.); (V.V.)
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Raj A, Chandran C S, Dua K, Kamath V, Alex AT. Targeting overexpressed surface proteins: A new strategy to manage the recalcitrant triple-negative breast cancer. Eur J Pharmacol 2024; 981:176914. [PMID: 39154820 DOI: 10.1016/j.ejphar.2024.176914] [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: 03/25/2024] [Revised: 08/08/2024] [Accepted: 08/15/2024] [Indexed: 08/20/2024]
Abstract
Triple-negative breast cancer (TNBC) is an aggressive and heterogeneous cancer that lacks all three molecular markers, Estrogen, Progesterone, and Human Epidermal Growth Factor Receptor 2 (HER2). This unique characteristic of TNBC makes it more resistant to hormonal therapy; hence, chemotherapy and surgery are preferred. Active targeting with nanoparticles is more effective in managing TNBC than a passive approach. The surface of TNBC cells overexpresses several cell-specific proteins, which can be explored for diagnostic and therapeutic purposes. Immunohistochemical analysis has revealed that TNBC cells overexpress αVβ3 integrin, Intercellular Adhesion Molecule 1 (ICAM-1), Glucose Transporter 5 (GLUT5), Transmembrane Glycoprotein Mucin 1 (MUC-1), and Epidermal Growth Factor Receptor (EGFR). These surface proteins can be targeted using ligands, such as aptamers, antibodies, and sugar molecules. Targeting the surface proteins of TNBC with ligands helps harmonize treatment and improve patient compliance. In this review, we discuss the proteins expressed, which are limited to αVβ3 integrin proteins, ICAM-1, GLUT-5, MUC1, and EGFR, on the surface of TNBC, the challenges associated with the preclinical setup of breast cancer for targeted nanoformulations, internalization techniques and their challenges, suggestions to overcome the limitations of successful translation of nanoparticles, and the possibility of ligand-conjugated nanoparticles targeting these surface receptors for a better therapeutic outcome.
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Affiliation(s)
- Alan Raj
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka state, India, 576104.
| | - Sarath Chandran C
- Department of Pharmaceutics, College of Pharmaceutical Sciences, Government Medical College Kannur, Pariyaram, Kerala, India, 670 503; Kerala University of Health Sciences, Thrissur, Kerala, India - 680 596.
| | - Kamal Dua
- Discipline of Pharmacy, Graduate School of Health, Faculty of Health, University of Technology Sydney, Sydney, Australia-2007; Australian Research Centre in Complementary and Integrative Medicine, Faculty of Health, University of Technology Sydney, Sydney, Australia-2007.
| | - Venkatesh Kamath
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka state, India, 576104.
| | - Angel Treasa Alex
- Department of Pharmaceutical Biotechnology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Udupi, Karnataka state, India, 576104.
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Huang C, Wang L, Wu G. Trefoil factor 1 (TFF1) reduces cerebral edema and gastric mucosal injury by regulating the EGFR/Src/FAK pathway in an intracerebral hemorrhage rat model. Neuropeptides 2024; 107:102460. [PMID: 39142164 DOI: 10.1016/j.npep.2024.102460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 08/01/2024] [Accepted: 08/01/2024] [Indexed: 08/16/2024]
Abstract
The destruction of the blood-brain barrier and damage to the gastrointestinal mucosa after intracerebral hemorrhage (ICH) are important reasons for its high disability and mortality rates. However, the exact etiology is not yet clear. In addition, there are currently no effective treatments for improving cerebral edema and gastric mucosal damage after ICH. Trefoil factor 1 (TFF1) is a secretory protein that plays a crucial role in maintaining the integrity and barrier function of the gastric mucosa, and it has been reported to have a protective effect on brain damage induced by various causes. This study utilized a rat model of ICH induced by type IV collagenase was utilized, and intervened with recombinant TFF1 protein from an external institute to investigate the protective mechanisms of TFF1 against brain edema and gastric mucosal damage after ICH. The results demonstrated that TFF1 alleviated the neurological function and gastric mucosal damage in the rat model of ICH induced by type IV collagenase. TFF1 may ensure the integrity of the blood-brain and gastric mucosal barriers by regulating the EGFR (epidermal growth factor receptor)/Src (non-receptor tyrosine kinase)/FAK (focal adhesion kinase) pathway. Clearly, the disruption of the blood-brain barrier and the destruction of the gastric mucosal barrier are key pathological features of ICH, and TFF1 can improve the progression of blood-brain barrier and gastric mucosal barrier disruption in ICH by regulating the EGFR/Src/FAK pathway. Therefore, TFF1 may be a potential target for the treatment of ICH.
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Affiliation(s)
- Chao Huang
- Emergency Department, Guizhou Medical University, Guiyang, Guizhou 550001, China; Department of Emergency Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China
| | - Likun Wang
- Emergency Department, Guizhou Medical University, Guiyang, Guizhou 550001, China; Department of Emergency Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China
| | - Guofeng Wu
- Emergency Department, Guizhou Medical University, Guiyang, Guizhou 550001, China; Department of Emergency Medicine, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou 550001, China.
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8
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Dickerson H, Diab A, Al Musaimi O. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Cancer: Current Use and Future Prospects. Int J Mol Sci 2024; 25:10008. [PMID: 39337496 PMCID: PMC11432255 DOI: 10.3390/ijms251810008] [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: 08/30/2024] [Revised: 09/12/2024] [Accepted: 09/16/2024] [Indexed: 09/30/2024] Open
Abstract
Tyrosine kinase inhibitors (TKIs) have emerged as a leading targeted cancer therapy, reducing the side effects often seen with non-targeted treatments, especially the damage to healthy cells. To tackle resistance, typically caused by epidermal growth factor receptor (EGFR) mutations, four generations of TKIs have been developed. Each generation has shown improved effectiveness and fewer side effects, resulting in better patient outcomes. For example, patients on gefitinib, a first-generation TKI, experienced a progression-free survival (PFS) of 10 months compared to 5 months with conventional chemotherapy. Second-generation TKI afatinib outperformed erlotinib and extended PFS to 11.1 months compared to 6.9 months with cisplatin. Third-generation TKIs further increased survival to 38.6 months, compared to 31.8 months with first-generation TKIs. This progress demonstrates the ability of newer TKIs to overcome resistance, particularly the T790M mutation, while reducing adverse effects. Ongoing research focuses on overcoming resistance from newer mutations like C797S to further improve patient survival. These developments highlight the significant progress in TKI therapy and the continued effort to refine cancer treatment. Recent research in South Korea shows that third-generation TKIs are ineffective against non-small cell lung cancer (NSCLC) with the C797S mutation. Several trials have started showing promising in vitro and in vivo results, but more trials are needed before clinical approval. This review underscores notable advancements in the field of EGFR TKIs, offering a comprehensive analysis of their mechanisms of action and the progression of various TKI generations in response to resistance.
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Affiliation(s)
- Henry Dickerson
- School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Ahmad Diab
- School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
| | - Othman Al Musaimi
- School of Pharmacy, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
- Department of Chemical Engineering, Imperial College London, London SW7 2AZ, UK
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Ketharanathan T, Pereira A, Sundram S. Gene expression changes in Brodmann's Area 46 differentiate epidermal growth factor and immune system interactions in schizophrenia and mood disorders. SCHIZOPHRENIA (HEIDELBERG, GERMANY) 2024; 10:76. [PMID: 39242583 PMCID: PMC11379811 DOI: 10.1038/s41537-024-00488-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Accepted: 07/16/2024] [Indexed: 09/09/2024]
Abstract
How early in life stress-immune related environmental factors increase risk predisposition to schizophrenia remains unknown. We examined if pro-inflammatory changes perturb the brain epidermal growth factor (EGF) system, a system critical for neurodevelopment and mature CNS functions including synaptic plasticity. We quantified genes from key EGF and immune system pathways for mRNA levels and eight immune proteins in post-mortem dorsolateral prefrontal (DLPFC; Brodmann's Area (BA) 46) and orbitofrontal (OFC; BA11) cortices from people with schizophrenia, mood disorders and neurotypical controls. In BA46, 64 genes were differentially expressed, predominantly in schizophrenia, where attenuated expression of the MAPK-ERK, NRG1-PI3K-AKT and mTOR cascades indicated reduced EGF system signalling, and similarly diminished immune molecular expression, notably in TLR, TNF and complement pathways, along with low NF-κB1 and elevated IL12RB2 protein levels were noted. There was nominal evidence for altered convergence between ErbB-PI3K-AKT-mTOR and TLR pathways in BA46 in schizophrenia. Comparatively minimal changes were noted in BA11. Overall, distinct pathway gene expression changes may reflect variant pathological processes involving immune and EGF system signalling between schizophrenia and mood disorder, particularly in DLPFC. Further, the abnormal convergence between innate immune signalling and candidate EGF signalling pathways may indicate a pathologically important interaction in the developing brain in response to environmental stressors.
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Affiliation(s)
- Tharini Ketharanathan
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia.
- Department of Psychiatry, University of Melbourne, Parkville, VIC 3052, Australia.
- Northern Health, Epping, VIC 3076, Australia.
| | - Avril Pereira
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, VIC 3052, Australia
- Department of Psychiatry, University of Melbourne, Parkville, VIC 3052, Australia
| | - Suresh Sundram
- Department of Psychiatry, School of Clinical Sciences, Monash University, Clayton, VIC 3168, Australia
- Mental Health Program, Monash Health, Clayton, VIC 3168, Australia
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10
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Papa F, Grinda T, Rassy E, Cheickh-Hussin R, Ribeiro J, Antonuzzo L, Pistilli B. Long road towards effective HER3 targeting in breast cancer. Cancer Treat Rev 2024; 129:102786. [PMID: 38885540 DOI: 10.1016/j.ctrv.2024.102786] [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: 03/21/2024] [Revised: 05/25/2024] [Accepted: 06/09/2024] [Indexed: 06/20/2024]
Abstract
Breast cancer is a heterogeneous disease, encompassing multiple different subtypes. Thanks to the increasing knowledge of the diverse biological features of each subtype, most patients receive personalized treatment based on known biomarkers. However, the role of some biomarkers in breast cancer evolution is still unknown, and their potential use as a therapeutic target is still underexplored. HER3 is a member of the human epidermal growth factors receptor family, overexpressed in 50%-70% of breast cancers. HER3 plays a key role in cancer progression, metastasis development, and drug resistance across all the breast cancer subtypes. Owing to its critical role in cancer progression, many HER3-targeting therapies have been developed over the past decade with conflicting findings. Next-generation antibody-drug conjugates have recently shown promising results in solid tumors expressing HER3, including breast cancer. In this review, we discuss the HER3 role in the pathogenesis of breast cancer and its relevance across all subtypes. We also explore the new anti-HER3 treatment strategies, calling into question the significance of HER3 detection as crucial information in breast cancer treatment.
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Affiliation(s)
- Francesca Papa
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France; Department of Medical Oncology, Florence University, Italy
| | - Thomas Grinda
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - Elie Rassy
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | | | - Joana Ribeiro
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | | | - Barbara Pistilli
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France; INSERM U1279, Gustave Roussy, Villejuif, France.
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11
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Cheng X. A Comprehensive Review of HER2 in Cancer Biology and Therapeutics. Genes (Basel) 2024; 15:903. [PMID: 39062682 PMCID: PMC11275319 DOI: 10.3390/genes15070903] [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: 06/01/2024] [Revised: 07/08/2024] [Accepted: 07/10/2024] [Indexed: 07/28/2024] Open
Abstract
Human epidermal growth factor receptor 2 (HER2), a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, plays a crucial role in cell proliferation, survival, and differentiation. Aberrant HER2 signaling is implicated in various cancers, particularly in breast and gastric cancers, where HER2 overexpression or amplification correlates with aggressive tumor behavior and poor prognosis. HER2-activating mutations contribute to accelerated tumorigenesis and metastasis. This review provides an overview of HER2 biology, signaling pathways, mechanisms of dysregulation, and diagnostic approaches, as well as therapeutic strategies targeting HER2 in cancer. Understanding the intricate details of HER2 regulation is essential for developing effective targeted therapies and improving patient outcomes.
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Affiliation(s)
- Xiaoqing Cheng
- Department of Oncology, School of Medicine, Washington University in Saint Louis, Saint Louis, MO 63108, USA
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12
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Ramos Solis N, Cannon A, Dilday T, Abt M, Oblak AL, Soloff AC, Kaplan MH, Yeh ES. HUNK as a key regulator of tumor-associated macrophages in triple negative breast cancer. Oncoimmunology 2024; 13:2364382. [PMID: 38846083 PMCID: PMC11155704 DOI: 10.1080/2162402x.2024.2364382] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Revised: 05/30/2024] [Accepted: 05/31/2024] [Indexed: 06/09/2024] Open
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC tumors are not sensitive to endocrine therapy, and standardized TNBC treatment regimens are lacking. TNBC is a more immunogenic subtype of breast cancer, making it more responsive to immunotherapy intervention. Tumor-associated macrophages (TAMs) constitute one of the most abundant immune cell populations in TNBC tumors and contribute to cancer metastasis. This study examines the role of the protein kinase HUNK in tumor immunity. Gene expression analysis using NanoString's nCounter PanCancer Immune Profiling panel identified that targeting HUNK is associated with changes in the IL-4/IL-4 R cytokine signaling pathway. Experimental analysis shows that HUNK kinase activity regulates IL-4 production in mammary tumor cells, and this regulation is dependent on STAT3. In addition, HUNK-dependent regulation of IL-4 secreted from tumor cells induces polarization of macrophages into an M2-like phenotype associated with TAMs. In return, IL-4 induces cancer metastasis and macrophages to produce epidermal growth factor. These findings delineate a paracrine signaling exchange between tumor cells and TAMs regulated by HUNK and dependent on IL-4/IL-4 R. This highlights the potential of HUNK as a target for reducing TNBC metastasis through modulation of the TAM population.
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Affiliation(s)
- Nicole Ramos Solis
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Anthony Cannon
- Department of Microbiology and Immunology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Tinslee Dilday
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Melissa Abt
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Adrian L. Oblak
- Department of Radiology and Imaging Sciences, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Adam C. Soloff
- Department of Cardiothoracic Surgery, University of Pittsburgh, Pittsburgh, PA, USA
| | - Mark H. Kaplan
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Department of Microbiology and Immunology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
| | - Elizabeth S. Yeh
- Department of Pharmacology and Toxicology, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
- Simon Comprehensive Cancer Center, Indiana University School of Medicine Indianapolis, Indianapolis, IN, USA
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13
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Yang F, Yan L, Ji J, Lou Y, Zhu J. HER2 puzzle pieces: Non-Coding RNAs as keys to mechanisms, chemoresistance, and clinical outcomes in Ovarian cancer. Pathol Res Pract 2024; 258:155335. [PMID: 38723327 DOI: 10.1016/j.prp.2024.155335] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Revised: 04/23/2024] [Accepted: 04/27/2024] [Indexed: 05/29/2024]
Abstract
Ovarian cancer (OC) presents significant challenges, characterized by limited treatment options and therapy resistance often attributed to dysregulation of the HER2 signaling pathway. Non-coding RNAs (ncRNAs) have emerged as key players in regulating gene expression in OC. This comprehensive review underscores the pivotal role of ncRNAs in modulating HER2 signaling, with a specific focus on their mechanisms, impact on chemoresistance, and prognostic/diagnostic implications. MicroRNAs, long non-coding RNAs, and circular RNAs have been identified as essential regulators in the modulation of the HER2 pathway. By directly targeting key components of the HER2 axis, these ncRNAs influence its activation and downstream signaling cascades. Dysregulated ncRNAs have been closely associated with chemoresistance, leading to treatment failures and disease progression in OC. Furthermore, distinct expression profiles of ncRNAs hold promise as reliable prognostic and diagnostic markers, facilitating personalized treatment strategies and enhancing disease outcome assessments. A comprehensive understanding of how ncRNAs intricately modulate HER2 signaling is imperative for the development of targeted therapies and the improvement of patient outcomes. The integration of ncRNA profiles into clinical practice has the potential to enhance prognostic and diagnostic accuracy in the management of ovarian cancer. Further research efforts are essential to validate the clinical utility of ncRNAs and elucidate their precise roles in the regulation of HER2 signaling. In conclusion, ncRNAs play a crucial role in governing HER2 signaling in ovarian cancer, impacting chemoresistance and providing valuable prognostic and diagnostic insights. The exploration of ncRNA-mediated HER2 modulation offers promising avenues for the development of personalized treatment approaches, ultimately advancing patient care and outcomes in OC.
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Affiliation(s)
- Fangwei Yang
- Obstetrical Department, Yiwu Central Hospital, Yiwu, Zhejiang 322000, China.
| | - Lixiang Yan
- Obstetrical Department, Yiwu Central Hospital, Yiwu, Zhejiang 322000, China
| | - Junnan Ji
- Obstetrical Department, Yiwu Central Hospital, Yiwu, Zhejiang 322000, China
| | - Yunxia Lou
- Obstetrical Department, Yiwu Central Hospital, Yiwu, Zhejiang 322000, China
| | - Jinlu Zhu
- Obstetrical Department, Yiwu Central Hospital, Yiwu, Zhejiang 322000, China
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14
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Thapa R, Afzal M, Goyal A, Gupta G, Bhat AA, Almalki WH, Kazmi I, Alzarea SI, Shahwan M, Kukreti N, Ali H, Dureja H, Kumar P, Singh TG, Kuppusamy G, Singh SK, Dua K. Exploring ncRNA-mediated regulation of EGFR signalling in glioblastoma: From mechanisms to therapeutics. Life Sci 2024; 345:122613. [PMID: 38582393 DOI: 10.1016/j.lfs.2024.122613] [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: 02/15/2024] [Revised: 04/03/2024] [Accepted: 04/03/2024] [Indexed: 04/08/2024]
Abstract
Glioblastoma (GBM) is the most prevalent and deadly primary brain tumor type, with a discouragingly low survival rate and few effective treatments. An important function of the EGFR signalling pathway in the development of GBM is to affect tumor proliferation, persistence, and treatment resistance. Advances in molecular biology in the last several years have shown how important ncRNAs are for controlling a wide range of biological activities, including cancer progression and development. NcRNAs have become important post-transcriptional regulators of gene expression, and they may affect the EGFR pathway by either directly targeting EGFR or by modifying important transcription factors and downstream signalling molecules. The EGFR pathway is aberrantly activated in response to the dysregulation of certain ncRNAs, which has been linked to GBM carcinogenesis, treatment resistance, and unfavourable patient outcomes. We review the literature on miRNAs, circRNAs and lncRNAs that are implicated in the regulation of EGFR signalling in GBM, discussing their mechanisms of action, interactions with the signalling pathway, and implications for GBM therapy. Furthermore, we explore the potential of ncRNA-based strategies to overcome resistance to EGFR-targeted therapies, including the use of ncRNA mimics or inhibitors to modulate the activity of key regulators within the pathway.
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Affiliation(s)
- Riya Thapa
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura 302017, Mahal Road, Jaipur, India
| | - Muhammad Afzal
- Department of Pharmaceutical Sciences, Pharmacy Program, Batterjee Medical College, P.O. Box 6231, Jeddah 21442, Saudi Arabia
| | - Ahsas Goyal
- Institute of Pharmaceutical Research, GLA University, Mathura, U.P., India
| | - Gaurav Gupta
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura 302017, Mahal Road, Jaipur, India; Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates.
| | - Asif Ahmad Bhat
- School of Pharmacy, Suresh Gyan Vihar University, Jagatpura 302017, Mahal Road, Jaipur, India
| | - Waleed Hassan Almalki
- Department of Pharmacology, College of Pharmacy, Umm Al-Qura University, Makkah, Saudi Arabia
| | - Imran Kazmi
- Department of Biochemistry, Faculty of Science, King Abdulaziz University, Jeddah, 21589, Saudi Arabia
| | - Sami I Alzarea
- Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf 72341, Saudi Arabia
| | - Moyad Shahwan
- Centre of Medical and Bio-allied Health Sciences Research, Ajman University, Ajman, United Arab Emirates; Department of Clinical Sciences, College of Pharmacy and Health Sciences, Ajman University, Ajman, 346, 7, United Arab Emirates
| | - Neelima Kukreti
- School of Pharmacy, Graphic Era Hill University, Dehradun 248007, India
| | - Haider Ali
- Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, India; Department of Pharmacology, Kyrgyz State Medical College, Bishkek, Kyrgyzstan
| | - Harish Dureja
- Department of Pharmaceutical Sciences, Maharshi Dayanand University, Rohtak 124001, Haryana, India
| | - Puneet Kumar
- Department of Pharmacology, Central University of Punjab, Ghudda, Punjab, India
| | - Thakur Gurjeet Singh
- Chitkara College of Pharmacy, Chitkara University, Rajpura, Punjab 140401, India
| | - Gowthamarajan Kuppusamy
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, Nilgiris, India
| | - Sachin Kumar Singh
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, Punjab 144411, India; Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia
| | - Kamal Dua
- Faculty of Health, Australian Research Centre in Complementary and Integrative Medicine, University of Technology Sydney, Ultimo, NSW 2007, Australia; Discipline of Pharmacy, Graduate School of Health, University of Technology Sydney, NSW 2007, Australia
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15
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Li Q, Li B, Wang Q, Wang C, Yu M, Xu T. Marine-derived EGFR inhibitors: novel compounds targeting breast cancer growth and drug resistance. Front Pharmacol 2024; 15:1396605. [PMID: 38751788 PMCID: PMC11094307 DOI: 10.3389/fphar.2024.1396605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2024] [Accepted: 04/15/2024] [Indexed: 05/18/2024] Open
Abstract
Breast cancer (BC) continues to be a major health challenge globally, ranking as the fifth leading cause of cancer mortality among women, despite advancements in cancer detection and treatment. In this study, we identified four novel compounds from marine organisms that effectively target and inhibit the Epidermal Growth Factor Receptor (EGFR), crucial for BC cell growth and proliferation. These compounds not only induced early apoptosis through Caspase-3 activation but also showed significant inhibitory effects on EGFR mutations associated with drug resistance (T790M, L858R, and L858R/T790M), demonstrating high EGFR kinase selectivity. Cell Thermal Shift Assay (CETSA) experiments indicated that Tandyukisin stabilizes EGFR in a concentration-dependent manner. Furthermore, binding competition assays using surface plasmon resonance technology revealed that Tandyukisin and Trichoharzin bound to distinct sites on EGFR and that their combined use enhanced apoptosis in BC cells. This discovery may pave the way for developing new marine-derived EGFR inhibitors, offering a promising avenue for innovative cancer treatment strategies and addressing EGFR-mediated drug resistance.
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Affiliation(s)
- Qi Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Bo Li
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Qian Wang
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
| | - Chengen Wang
- Department of Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
| | - Miao Yu
- Engineering Research Center for Medicine, Ministry of Education, Harbin University of Commerce, Harbin, China
| | - Tianfu Xu
- State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Beijing, China
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16
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Li X, Yao J, Qu C, Luo L, Li B, Zhang Y, Zhu Z, Qiu Y, Hua H. DB-1310, an ADC comprised of a novel anti-HER3 antibody conjugated to a DNA topoisomerase I inhibitor, is highly effective for the treatment of HER3-positive solid tumors. J Transl Med 2024; 22:362. [PMID: 38632563 PMCID: PMC11022355 DOI: 10.1186/s12967-024-05133-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Accepted: 03/24/2024] [Indexed: 04/19/2024] Open
Abstract
BACKGROUND HER3 (ErbB3), a member of the human epidermal growth factor receptor family, is frequently overexpressed in various cancers. Multiple HER3-targeting antibodies and antibody-drug conjugates (ADCs) were developed for the solid tumor treatment, however none of HER3-targeting agent has been approved for tumor therapy yet. We developed DB-1310, a HER3 ADC composed of a novel humanized anti-HER3 monoclonal antibody covalently linked to a proprietary DNA topoisomerase I inhibitor payload (P1021), and evaluate the efficacy and safety of DB-1310 in preclinical models. METHODS The binding of DB-1310 to Her3 and other HER families were measured by ELISA and SPR. The competition of binding epitope for DB-1310 and patritumab was tested by FACS. The sensitivity of breast, lung, prostate and colon cancer cell lines to DB-1310 was evaluated by in vitro cell killing assay. In vivo growth inhibition study evaluated the sensitivity of DB-1310 to Her3 + breast, lung, colon and prostate cancer xenograft models. The safety profile was also measured in cynomolgus monkey. RESULTS DB-1310 binds HER3 via a novel epitope with high affinity and internalization capacity. In vitro, DB-1310 exhibited cytotoxicity in numerous HER3 + breast, lung, prostate and colon cancer cell lines. In vivo studies in HER3 + HCC1569 breast cancer, NCI-H441 lung cancer and Colo205 colon cancer xenograft models showed DB-1310 to have dose-dependent tumoricidal activity. Tumor suppression was also observed in HER3 + non-small cell lung cancer (NSCLC) and prostate cancer patient-derived xenograft (PDX) models. Moreover, DB-1310 showed stronger tumor growth-inhibitory activity than patritumab deruxtecan (HER3-DXd), which is another HER3 ADC in clinical development at the same dose. The tumor-suppressive activity of DB-1310 synergized with that of EGFR tyrosine kinase inhibitor, osimertinib, and exerted efficacy also in osimertinib-resistant PDX model. The preclinical assessment of safety in cynomolgus monkeys further revealed DB-1310 to have a good safety profile with a highest non severely toxic dose (HNSTD) of 45 mg/kg. CONCLUSIONS These finding demonstrated that DB-1310 exerted potent antitumor activities against HER3 + tumors in in vitro and in vivo models, and showed acceptable safety profiles in nonclinical species. Therefore, DB-1310 may be effective for the clinical treatment of HER3 + solid tumors.
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Affiliation(s)
- Xi Li
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China.
| | - Jun Yao
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Chen Qu
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Lan Luo
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Bing Li
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Yu Zhang
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Zhongyuan Zhu
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Yang Qiu
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China
| | - Haiqing Hua
- Department of Research and Development, Duality Biologics, LTD, Unite 1106 868 Yinghua Road, Shanghai, 201204, P.R. China.
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17
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Kwon Y, Kang M, Jeon YM, Lee S, Lee HW, Park JS, Kim HJ. Identification and characterization of novel ERBB4 variant associated with sporadic amyotrophic lateral sclerosis (ALS). J Neurol Sci 2024; 457:122885. [PMID: 38278691 DOI: 10.1016/j.jns.2024.122885] [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: 09/26/2023] [Revised: 01/11/2024] [Accepted: 01/11/2024] [Indexed: 01/28/2024]
Abstract
Amyotrophic Lateral Sclerosis (ALS) is the most common type of motor neuron disease characterized by progressive motor neuron degeneration in brain and spinal cord. Most cases are sporadic in ALS and 5-10% of cases are familiar. >50 genes are known to be associated with ALS and one of them is ERBB4. In this paper, we report the case of a 53-year-old ALS patient with progressive muscle weakness and fasciculation, but he had no cognitive decline. We performed the next generation sequencing (NGS) and in silico analysis, it predicted a highly pathogenic variant, c.2116 A > G, p.Asn706Asp (N706D) in the ERBB4 gene. The amino acid residue is highly conserved among species. ERBB4 is a member of the ERBB family of receptor tyrosine kinases. ERBB4 has multiple tyrosine phosphorylation sites, including an autophosphorylation site at tyrosine 1284 residue. Autophosphorylation of ERBB4 promotes biological activity and it associated with NRG-1/ERBB4 pathway. It is already known that tyrosine 128 phosphorylation of ERBB4 is decreased in patients who have ALS-associated ERBB4 mutations. We generated ERBB4 N706D construct using site-directed mutagenesis and checked the phosphorylation level of ERBB4 N706D in NSC-34 cells. We found that the phosphorylation of ERBB4 N706D was decreased compared to ERBB4 wild-type, indicating a loss of function mutation in ERBB4. We report a novel variant in ERBB4 gene leading to ALS through dysfunction of ERBB4.
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Affiliation(s)
- Younghwi Kwon
- Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea
| | - Minsung Kang
- Department of Neurology, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea
| | - Yu-Mi Jeon
- Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea
| | - Shinrye Lee
- Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea
| | - Ho-Won Lee
- Department of Neurology, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu, Republic of Korea
| | - Jin-Sung Park
- Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; Brain Science & Engineering Institute, Kyungpook National University, Daegu, Republic of Korea.
| | - Hyung-Jun Kim
- Dementia Research Group, Korea Brain Research Institute (KBRI), Daegu, South Korea; Department of Brain Sciences, DGIST, Daegu, South Korea.
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18
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Lee CH, Park S, Kim S, Hyun JY, Lee HS, Shin I. Engineering of cell-surface receptors for analysis of receptor internalization and detection of receptor-specific glycosylation. Chem Sci 2024; 15:555-565. [PMID: 38179521 PMCID: PMC10762726 DOI: 10.1039/d3sc05054h] [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: 09/26/2023] [Accepted: 12/06/2023] [Indexed: 01/06/2024] Open
Abstract
The epidermal growth factor receptor (EGFR) is a cell-surface glycoprotein that is involved mainly in cell proliferation. Overexpression of this receptor is intimately related to the development of a broad spectrum of tumors. In addition, glycans linked to the EGFR are known to affect its EGF-induced activation. Because of the pathophysiological significance of the EGFR, we prepared a fluorescently labeled EGFR (EGFR128-AZDye 488) on the cell surface by employing the genetic code expansion technique and bioorthogonal chemistry. EGFR128-AZDye 488 was initially utilized to investigate time-dependent endocytosis of the EGFR in live cells. The results showed that an EGFR inhibitor and antibody suppress endocytosis of the EGFR promoted by the EGF, and that lectins recognizing glycans of the EGFR do not enhance EGFR internalization into cells. Observations made in studies of the effects of appended glycans on the entry of the EGFR into cells indicate that a de-sialylated or de-fucosylated EGFR is internalized into cells more efficiently than a wild-type EGFR. Furthermore, by using the FRET-based imaging method of cells which contain an EGFR linked to AZDye 488 (a FRET donor) and cellular glycans labeled with rhodamine (a FRET acceptor), sialic acid residues attached to the EGFR were specifically detected on the live cell surface. Taken together, the results suggest that a fluorescently labeled EGFR will be a valuable tool in studies aimed at gaining an understanding of cellular functions of the EGFR.
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Affiliation(s)
- Chang-Hee Lee
- Department of Chemistry, Yonsei University Seoul 03722 Republic of Korea
| | - Sookil Park
- Department of Chemistry, Yonsei University Seoul 03722 Republic of Korea
| | - Sanggil Kim
- Department of Chemistry, Sogang University Seoul 04107 Republic of Korea
| | - Ji Young Hyun
- Data Convergence Drug Research Center, Korea Research Institute of Chemical Technology Daejeon 34114 Republic of Korea
| | - Hyun Soo Lee
- Department of Chemistry, Sogang University Seoul 04107 Republic of Korea
| | - Injae Shin
- Department of Chemistry, Yonsei University Seoul 03722 Republic of Korea
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19
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Hajjo R, Sabbah DA, Bardaweel SK, Zhong HA. Targeting the EGFR/RAS/RAF signaling pathway in anticancer research: a recent update on inhibitor design and clinical trials (2020-2023). Expert Opin Ther Pat 2024; 34:51-69. [PMID: 38450537 DOI: 10.1080/13543776.2024.2327307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/25/2024] [Indexed: 03/08/2024]
Abstract
INTRODUCTION Recent years have seen significant strides in drug developmenttargeting the EGFR/RAS/RAF signaling pathway which is critical forcell growth and proliferation. Protein-protein interaction networksamong EGFR, RAS, and RAF proteins offer insights for drug discovery. This review discusses the drug design and development efforts ofinhibitors targeting these proteins over the past 3 years, detailingtheir structures, selectivity, efficacy, and combination therapy.Strategies to combat drug resistance and minimize toxicities areexplored, along with future research directions. AREA COVERED This review encompasses clinical trials and patents on EGFR, KRAS,and BRAF inhibitors from 2020 to 2023, including advancements indesign and synthesis of proteolysis targeting chimeras (PROTACs) forprotein degradation. EXPERT OPINION To tackle drug resistance, designing allosteric fourth-generationEGFR inhibitors is vital. Covalent, allosteric, or combinationaltherapies, along with PROTAC degraders, are key methods to addressresistance and toxicity in KRAS and BRAF inhibitors.
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Affiliation(s)
- Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
- Laboratory for Molecular Modeling, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- Board Member, National Center for Epidemics and Communicable Disease Control (JCDC), Amman, Jordan
| | - Dima A Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, Amman, Jordan
| | - Sanaa K Bardaweel
- Department of Pharmaceutical Sciences, School of Pharmacy, University of Jordan, Amman, Jordan
| | - Haizhen A Zhong
- DSC 309, Department of Chemistry, The University of Nebraska at Omaha, Omaha, NE, USA
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20
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Zheng L, Luthra R, Alvarez HA, San Lucas FA, Duose DY, Wistuba II, Fuller GN, Ballester LY, Roy-Chowdhuri S, Sweeney KJ, Rashid A, Yang RK, Chen W, Liu A, Wu Y, Albarracin C, Patel KP, Routbort MJ, Sahin AA, Ding Q, Chen H. Intragenic EGFR::EGFR.E1E8 Fusion (EGFRvIII) in 4331 Solid Tumors. Cancers (Basel) 2023; 16:6. [PMID: 38201434 PMCID: PMC10778229 DOI: 10.3390/cancers16010006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Revised: 12/01/2023] [Accepted: 12/06/2023] [Indexed: 01/12/2024] Open
Abstract
Epidermal growth factor receptor variant III (EGFRvIII, the deletion of exons 2-7) is a recurrent intragenic EGFR::EGFR.E1E8 fusion that occurs in high-grade gliomas. The presence of EGFRvIII in other solid tumors has not been well characterized. We retrospectively reviewed advanced malignant solid tumor cases tested by a custom hybrid capture 610-gene next-generation sequencing platform from 2021 to 2022. EGFRvIII was identified in 17 of 4331 (0.4%) cases, including 16 of 238 (7%) brain tumors and 1/301 (0.3%) breast tumors. EGFRvIII-positive brain tumors were all glioblastoma IDH-wildtype, most with concurrent TERT promoter mutation (14 of 16), EGFR amplification (13 of 16), and EGFR mutation (8 of 16). The only EGFRvIII-positive breast lesion was a sarcomatoid neoplasm in a young female patient. A separate breast case tested outside our institution with reported EGFRvIII was noted in a young female patient with a malignant phyllodes tumor with stromal overgrowth. Microscopically, both EGFRvIII-positive breast tumors showed high-grade sarcomatoid morphology with brisk mitotic activity. In summary, EGFRvIII is rare, occurring primarily in glioblastoma and rarely in breast sarcomatoid neoplasm, with no instances identified in other tumor types in our series. This select group of patients may benefit from chemotherapy and/or targeted anti-EGFR therapy.
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Affiliation(s)
- Lan Zheng
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Rajyalakshmi Luthra
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (H.A.A.)
| | - Hector A. Alvarez
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (H.A.A.)
| | - F. Anthony San Lucas
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (H.A.A.)
| | - Dzifa Y. Duose
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (I.I.W.)
| | - Ignacio I. Wistuba
- Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (I.I.W.)
| | - Gregory N. Fuller
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Leomar Y. Ballester
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Sinchita Roy-Chowdhuri
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Keith J. Sweeney
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Richard K. Yang
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Wei Chen
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (H.A.A.)
| | - Audrey Liu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Yun Wu
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Constance Albarracin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Keyur P. Patel
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (H.A.A.)
| | - Mark J. Routbort
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (H.A.A.)
| | - Aysegul A. Sahin
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Qingqing Ding
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
| | - Hui Chen
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA (Y.W.); (C.A.); (A.A.S.)
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Li T, Ling J, Du X, Zhang S, Yang Y, Zhang L. Exploring the underlying mechanisms of fisetin in the treatment of hepatic insulin resistance via network pharmacology and in vitro validation. Nutr Metab (Lond) 2023; 20:51. [PMID: 37996895 PMCID: PMC10666360 DOI: 10.1186/s12986-023-00770-z] [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: 06/07/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
OBJECTIVE To characterize potential mechanisms of fisetin on hepatic insulin resistance (IR) using network pharmacology and in vitro validation. METHODS Putative targets of fisetin were retrieved from the Traditional Chinese Medicine Systems Pharmacology database, whereas the potential genes of hepatic IR were obtained from GeneCards database. A protein-protein interaction (PPI) network was constructed according to the intersection targets of fisetin and hepatic IR using the Venn diagram. The biological functions and potential pathways related to genes were determined using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Cell experiments were also conducted to further verify the mechanism of fisetin on hepatic IR. RESULTS A total of 118 potential targets from fisetin were associated with hepatic IR. The areas of nodes and corresponding degree values of TP53, AKT1, TNF, IL6, CASP3, CTNNB1, JUN, SRC, epidermal growth factor receptor (EGFR), and HSP90AA1 were larger and could be easily found in the PPI network. Furthermore, GO analysis revealed that these key targets were significantly involved in multiple biological processes that participated in oxidative stress and serine/threonine kinase activity. KEGG enrichment analysis showed that the PI3K/AKT signaling pathway was a significant pathway involved in hepatic IR. Our in vitro results demonstrated that fisetin treatment increased the expressions of EGFR and IRS in HepG2 and L02 cells under normal or IR conditions. Western blot results revealed that p-AKT/AKT levels were significantly up-regulated, suggesting that fisetin was involved in the PI3K/AKT signaling pathway to regulate insulin signaling. CONCLUSION We explored the pharmacological actions and the potential molecular mechanism of fisetin in treating hepatic IR from a holistic perspective. Our study lays a theoretical foundation for the development of fisetin for type 2 diabetes.
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Affiliation(s)
- Tian Li
- Metabilic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, China
- School of Medicine, University of Electronic Science and Technology of China, Chengdu, 610000, China
| | - Junjun Ling
- Affiliated Hospital of Guizhou Medical University, Guiyang, 550000, China
| | - Xingrong Du
- Metabilic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, China
| | - Siyu Zhang
- Drug Discovery Research Center, Southwest Medical University, Luzhou, 646000, China
| | - Yan Yang
- Chongqing Tongnan NO.1 Middle School, Tongnan, 402660, China
| | - Liang Zhang
- Metabilic Vascular Disease Key Laboratory of Sichuan Province, Luzhou, 646000, China.
- Affiliated Hospital of Guizhou Medical University, Guiyang, 550000, China.
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22
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Tang G, Wang W, Wang X, Ding K, Ngan SC, Chen JY, Sze SK, Gao L, Yuan P, Lu X, Yao SQ. Cell-active, irreversible covalent inhibitors that selectively target the catalytic lysine of EGFR by using fluorosulfate-based SuFEx chemistry. Eur J Med Chem 2023; 259:115671. [PMID: 37499291 DOI: 10.1016/j.ejmech.2023.115671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/09/2023] [Accepted: 07/19/2023] [Indexed: 07/29/2023]
Abstract
EGFR signaling is involved in multiple cellular processes including cell proliferation, differentiation and development, making this protein kinase one of the most valuable drug targets for the treatment of non-small cell lung carcinomas (NSCLC). Herein, we describe the design and synthesis of a series of potential covalent inhibitors targeting the catalytically conserved lysine (K745) of EGFR on the basis of Erlotinib, an FDA-approved first-generation EGFR drug. Different amine-reactive electrophiles were introduced at positions on the Erlotinib scaffold proximal to K745 in EGFR. The optimized compound 26 (as well as its close analog 30), possessing a novel arylfluorosulfate group (ArOSO2F), showed excellent in vitro potency (as low as 0.19 nM in independent IC50 determination) and selectivity against EGFR and many of its drug-resistant mutants. Both intact protein mass spectrometry (MS) and site-mapping analysis revealed that compound 26 covalently bound to EGFR at K745 through the formation of a sulfamate. In addition, compound 26 displayed good anti-proliferative potency against EGFR-overexpressing HCC827 cells by inhibiting endogenous EGFR autophosphorylation. The pharmacokinetic studies of compound 26 demonstrated the druggable potential of other ArOSO2F-containing compounds. Finally, competitive activity-based protein profiling (ABPP), cellular thermal shift assay (CETSA), as well as cellular wash-out experiments, all showed compound 26 to be the first cell-active, fluorosulfate-based targeted covalent inhibitor (TCI) of protein kinases capable of covalently engaging the catalytically conserved lysine of its target in live mammalian cells.
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Affiliation(s)
- Guanghui Tang
- Department of Chemistry, National University of Singapore, Singapore, 117543, Singapore
| | - Wei Wang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518000, China
| | - Xuan Wang
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518000, China
| | - Ke Ding
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China; State Key Laboratory of Bioorganic & Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, 200032, China
| | - SoFong Cam Ngan
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, Ontario, L2S 3A1, Canada
| | - Jiao-Yu Chen
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518000, China
| | - Siu Kwan Sze
- Department of Health Sciences, Faculty of Applied Health Sciences, Brock University, St. Catharines, Ontario, L2S 3A1, Canada
| | - Liqian Gao
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518000, China
| | - Peiyan Yuan
- School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen, 518000, China.
| | - Xiaoyun Lu
- International Cooperative Laboratory of Traditional Chinese Medicine Modernization and Innovative Drug Discovery of Chinese Ministry of Education (MOE), Guangzhou City Key Laboratory of Precision Chemical Drug Development, School of Pharmacy, Jinan University, Guangzhou, 510632, China.
| | - Shao Q Yao
- Department of Chemistry, National University of Singapore, Singapore, 117543, Singapore.
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23
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Dewdney B, Jenkins MR, Best SA, Freytag S, Prasad K, Holst J, Endersby R, Johns TG. From signalling pathways to targeted therapies: unravelling glioblastoma's secrets and harnessing two decades of progress. Signal Transduct Target Ther 2023; 8:400. [PMID: 37857607 PMCID: PMC10587102 DOI: 10.1038/s41392-023-01637-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Revised: 08/29/2023] [Accepted: 09/07/2023] [Indexed: 10/21/2023] Open
Abstract
Glioblastoma, a rare, and highly lethal form of brain cancer, poses significant challenges in terms of therapeutic resistance, and poor survival rates for both adult and paediatric patients alike. Despite advancements in brain cancer research driven by a technological revolution, translating our understanding of glioblastoma pathogenesis into improved clinical outcomes remains a critical unmet need. This review emphasises the intricate role of receptor tyrosine kinase signalling pathways, epigenetic mechanisms, and metabolic functions in glioblastoma tumourigenesis and therapeutic resistance. We also discuss the extensive efforts over the past two decades that have explored targeted therapies against these pathways. Emerging therapeutic approaches, such as antibody-toxin conjugates or CAR T cell therapies, offer potential by specifically targeting proteins on the glioblastoma cell surface. Combination strategies incorporating protein-targeted therapy and immune-based therapies demonstrate great promise for future clinical research. Moreover, gaining insights into the role of cell-of-origin in glioblastoma treatment response holds the potential to advance precision medicine approaches. Addressing these challenges is crucial to improving outcomes for glioblastoma patients and moving towards more effective precision therapies.
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Affiliation(s)
- Brittany Dewdney
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia.
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia.
| | - Misty R Jenkins
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Sarah A Best
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Saskia Freytag
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
| | - Krishneel Prasad
- Immunology Division, The Walter and Eliza Hall Institute of Medical Research, Melbourne, 3052, Australia
- Department of Medical Biology, University of Melbourne, Melbourne, 3010, Australia
| | - Jeff Holst
- School of Biomedical Sciences, University of New South Wales, Sydney, 2052, Australia
| | - Raelene Endersby
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
| | - Terrance G Johns
- Cancer Centre, Telethon Kids Institute, Nedlands, WA, 6009, Australia
- Centre For Child Health Research, University of Western Australia, Perth, WA, 6009, Australia
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24
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Xie X, Yu T, Li X, Zhang N, Foster LJ, Peng C, Huang W, He G. Recent advances in targeting the "undruggable" proteins: from drug discovery to clinical trials. Signal Transduct Target Ther 2023; 8:335. [PMID: 37669923 PMCID: PMC10480221 DOI: 10.1038/s41392-023-01589-z] [Citation(s) in RCA: 112] [Impact Index Per Article: 56.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 07/22/2023] [Accepted: 08/02/2023] [Indexed: 09/07/2023] Open
Abstract
Undruggable proteins are a class of proteins that are often characterized by large, complex structures or functions that are difficult to interfere with using conventional drug design strategies. Targeting such undruggable targets has been considered also a great opportunity for treatment of human diseases and has attracted substantial efforts in the field of medicine. Therefore, in this review, we focus on the recent development of drug discovery targeting "undruggable" proteins and their application in clinic. To make this review well organized, we discuss the design strategies targeting the undruggable proteins, including covalent regulation, allosteric inhibition, protein-protein/DNA interaction inhibition, targeted proteins regulation, nucleic acid-based approach, immunotherapy and others.
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Affiliation(s)
- Xin Xie
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Tingting Yu
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Xiang Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
| | - Nan Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China
- Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Leonard J Foster
- Michael Smith Laboratories, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China.
| | - Wei Huang
- State Key Laboratory of Southwestern Chinese Medicine Resources, College of Medical Technology and School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 611137, Chengdu, China.
| | - Gu He
- Department of Dermatology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, 610041, Chengdu, China.
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25
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Lefebvre C, Pellizzari S, Bhat V, Jurcic K, Litchfield DW, Allan AL. Involvement of the AKT Pathway in Resistance to Erlotinib and Cabozantinib in Triple-Negative Breast Cancer Cell Lines. Biomedicines 2023; 11:2406. [PMID: 37760847 PMCID: PMC10525382 DOI: 10.3390/biomedicines11092406] [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: 06/29/2023] [Revised: 08/14/2023] [Accepted: 08/26/2023] [Indexed: 09/29/2023] Open
Abstract
Resistance to protein tyrosine kinase inhibitors (TKIs) presents a significant challenge in therapeutic target development for cancers such as triple-negative breast cancer (TNBC), where conventional therapies are ineffective at combatting systemic disease. Due to increased expression, the receptor tyrosine kinases EGFR (epidermal growth factor receptor) and c-Met are potential targets for treatment. However, targeted anti-EGFR and anti-c-Met therapies have faced mixed results in clinical trials due to acquired resistance. We hypothesize that adaptive responses in regulatory kinase networks within the EGFR and c-Met signaling axes contribute to the development of acquired erlotinib and cabozantinib resistance. To test this, we developed two separate models for cabozantinib and erlotinib resistance using the MDA-MB-231 and MDA-MB-468 cell lines, respectively. We observed that erlotinib- or cabozantinib-resistant cell lines demonstrate enhanced cell proliferation, migration, invasion, and activation of EGFR or c-Met downstream signaling (respectively). Using a SILAC (Stable Isotope Labeling of Amino acids in Cell Culture)-labeled quantitative mass spectrometry proteomics approach, we assessed the effects of erlotinib or cabozantinib resistance on the phosphoproteome, proteome, and kinome. Using this integrated proteomics approach, we identified several potential kinase mediators of cabozantinib resistance and confirmed the contribution of AKT1 to erlotinib resistance in TNBC-resistant cell lines.
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Affiliation(s)
- Cory Lefebvre
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Sierra Pellizzari
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Vasudeva Bhat
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
| | - Kristina Jurcic
- Department of Biochemistry, Western University, London, ON N6A 3K7, Canada; (K.J.); (D.W.L.)
| | - David W. Litchfield
- Department of Biochemistry, Western University, London, ON N6A 3K7, Canada; (K.J.); (D.W.L.)
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
| | - Alison L. Allan
- London Regional Cancer Program, London Health Sciences Centre, London, ON N6A 5W9, Canada; (C.L.); (S.P.); (V.B.)
- Department of Anatomy & Cell Biology, Western University, London, ON N6A 3K7, Canada
- Department of Oncology, Western University, London, ON N6A 3K7, Canada
- Lawson Health Research Institute, London, ON N6A 5W9, Canada
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26
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Lee JH, Kim J, Kim JO, Kwon YJ. Association of non-high-density lipoprotein cholesterol trajectories with the development of non-alcoholic fatty liver disease: an epidemiological and genome-wide association study. J Transl Med 2023; 21:435. [PMID: 37403158 DOI: 10.1186/s12967-023-04291-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Accepted: 06/20/2023] [Indexed: 07/06/2023] Open
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) shares common risk factors with cardiovascular diseases. Effects of longitudinal trends in non-high-density lipoprotein (non-HDL) cholesterol on NAFLD development are not understood. This study aimed to assess the relationship between non-HDL cholesterol trajectories and the incidence of NAFLD and to identify genetic differences contributing to NAFLD development between non-HDL cholesterol trajectory groups. METHODS We analyzed data from 2203 adults (aged 40-69 years) who participated in the Korean Genome and Epidemiology Study. During the 6-year exposure periods, participants were classified into an increasing non-HDL cholesterol trajectory group (n = 934) or a stable group (n = 1269). NAFLD was defined using a NAFLD-liver fat score > -0.640. Multiple Cox proportional hazard regression analysis estimated the hazard ratio (HR) and the 95% confidence interval (CI) for the incidence of NAFLD in the increasing group compared with the stable group. RESULTS A genome-wide association study identified significant single-nucleotide polymorphisms (SNPs) associated with NAFLD. During the median 7.8-year of event accrual period, 666 (30.2%) newly developed NAFLD cases were collected. Compared with the stable non-HDL group, the adjusted HR (95% CI) for the incidence of NAFLD in the increasing non-HDL cholesterol group was 1.46 (1.25-1.71). Although there were no significant SNPs, the polygenic risk score was highest in the increasing group, followed by the stable and control groups. CONCLUSION Our study indicates that lifestyle or environmental factors have a greater effect size than genetic factors in NAFLD progression risk. Lifestyle modification could be an effective prevention strategy for NAFLD for people with elevated non-HDL cholesterol.
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Affiliation(s)
- Jun-Hyuk Lee
- Department of Family Medicine, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, 01830, Republic of Korea
- Department of Medicine, Hanyang University Graduate School of Medicine, Seoul, 04763, Republic of Korea
| | - Jiyeon Kim
- Institute of Genetic Epidemiology, basgenbio Inc., 64, Keunumul-Ro, Mapo-Gu, Seoul, 04166, Republic of Korea
| | - Jung Oh Kim
- Institute of Genetic Epidemiology, basgenbio Inc., 64, Keunumul-Ro, Mapo-Gu, Seoul, 04166, Republic of Korea.
| | - Yu-Jin Kwon
- Department of Family Medicine, Yongin Severance Hospital, Yonsei University College of Medicine, 363, Dongbaekjukjeon-daero, Giheung-gu, Yongin-si, Gyeonggi-do, 16995, Republic of Korea.
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27
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Steele TM, Tsamouri MM, Siddiqui S, Lucchesi CA, Vasilatis D, Mooso BA, Durbin-Johnson BP, Ma AH, Hejazi N, Parikh M, Mudryj M, Pan CX, Ghosh PM. Cisplatin-induced increase in heregulin 1 and its attenuation by the monoclonal ErbB3 antibody seribantumab in bladder cancer. Sci Rep 2023; 13:9617. [PMID: 37316561 PMCID: PMC10267166 DOI: 10.1038/s41598-023-36774-1] [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: 11/13/2022] [Accepted: 06/09/2023] [Indexed: 06/16/2023] Open
Abstract
Cisplatin-based combination chemotherapy is the foundation for treatment of advanced bladder cancer (BlCa), but many patients develop chemoresistance mediated by increased Akt and ERK phosphorylation. However, the mechanism by which cisplatin induces this increase has not been elucidated. Among six patient-derived xenograft (PDX) models of BlCa, we observed that the cisplatin-resistant BL0269 express high epidermal growth factor receptor, ErbB2/HER2 and ErbB3/HER3. Cisplatin treatment transiently increased phospho-ErbB3 (Y1328), phospho-ERK (T202/Y204) and phospho-Akt (S473), and analysis of radical cystectomy tissues from patients with BlCa showed correlation between ErbB3 and ERK phosphorylation, likely due to the activation of ERK via the ErbB3 pathway. In vitro analysis revealed a role for the ErbB3 ligand heregulin1-β1 (HRG1/NRG1), which is higher in chemoresistant lines compared to cisplatin-sensitive cells. Additionally, cisplatin treatment, both in PDX and cell models, increased HRG1 levels. The monoclonal antibody seribantumab, that obstructs ErbB3 ligand-binding, suppressed HRG1-induced ErbB3, Akt and ERK phosphorylation. Seribantumab also prevented tumor growth in both the chemosensitive BL0440 and chemoresistant BL0269 models. Our data demonstrate that cisplatin-associated increases in Akt and ERK phosphorylation is mediated by an elevation in HRG1, suggesting that inhibition of ErbB3 phosphorylation may be a useful therapeutic strategy in BlCa with high phospho-ErbB3 and HRG1 levels.
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Affiliation(s)
- Thomas M Steele
- Research Service, VA Northern California Health Care System, Mather, CA, USA
- Department of Urological Surgery, University of California Davis School of Medicine, 4860 Y Street, Suite 3500, Sacramento, CA, 95817, USA
| | - Maria Malvina Tsamouri
- Research Service, VA Northern California Health Care System, Mather, CA, USA
- Department of Urological Surgery, University of California Davis School of Medicine, 4860 Y Street, Suite 3500, Sacramento, CA, 95817, USA
| | - Salma Siddiqui
- Research Service, VA Northern California Health Care System, Mather, CA, USA
| | - Christopher A Lucchesi
- Research Service, VA Northern California Health Care System, Mather, CA, USA
- Surgical and Radiological Sciences, School of Veterinary Medicine, University of California Davis, Davis, USA
| | - Demitria Vasilatis
- Research Service, VA Northern California Health Care System, Mather, CA, USA
- Department of Urological Surgery, University of California Davis School of Medicine, 4860 Y Street, Suite 3500, Sacramento, CA, 95817, USA
| | - Benjamin A Mooso
- Research Service, VA Northern California Health Care System, Mather, CA, USA
| | - Blythe P Durbin-Johnson
- Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Davis, CA, USA
| | - Ai-Hong Ma
- Department of Biochemistry and Molecular Medicine, University of California Davis, Sacramento, CA, USA
| | - Nazila Hejazi
- Research Service, VA Northern California Health Care System, Mather, CA, USA
- Yosemite Pathology Medical Group, Inc., Modesto, CA, USA
| | - Mamta Parikh
- Division of Hematology and Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA
| | - Maria Mudryj
- Research Service, VA Northern California Health Care System, Mather, CA, USA
- Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA
| | - Chong-Xian Pan
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Paramita M Ghosh
- Research Service, VA Northern California Health Care System, Mather, CA, USA.
- Department of Urological Surgery, University of California Davis School of Medicine, 4860 Y Street, Suite 3500, Sacramento, CA, 95817, USA.
- Division of Biostatistics, Department of Public Health Sciences, University of California Davis, Davis, CA, USA.
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28
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Bi J, Wu Z, Zhang X, Zeng T, Dai W, Qiu N, Xu M, Qiao Y, Ke L, Zhao J, Cao X, Lin Q, Chen XL, Xie L, Ouyang Z, Guo J, Zheng L, Ma C, Guo S, Chen K, Mo W, Fu G, Zhao TJ, Wang HR. TMEM25 inhibits monomeric EGFR-mediated STAT3 activation in basal state to suppress triple-negative breast cancer progression. Nat Commun 2023; 14:2342. [PMID: 37095176 PMCID: PMC10126118 DOI: 10.1038/s41467-023-38115-2] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 04/17/2023] [Indexed: 04/26/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with poor outcome and lacks of approved targeted therapy. Overexpression of epidermal growth factor receptor (EGFR) is found in more than 50% TNBC and is suggested as a driving force in progression of TNBC; however, targeting EGFR using antibodies to prevent its dimerization and activation shows no significant benefits for TNBC patients. Here we report that EGFR monomer may activate signal transducer activator of transcription-3 (STAT3) in the absence of transmembrane protein TMEM25, whose expression is frequently decreased in human TNBC. Deficiency of TMEM25 allows EGFR monomer to phosphorylate STAT3 independent of ligand binding, and thus enhances basal STAT3 activation to promote TNBC progression in female mice. Moreover, supplying TMEM25 by adeno-associated virus strongly suppresses STAT3 activation and TNBC progression. Hence, our study reveals a role of monomeric-EGFR/STAT3 signaling pathway in TNBC progression and points out a potential targeted therapy for TNBC.
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Affiliation(s)
- Jing Bi
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Zhihui Wu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Xin Zhang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
- State Key Laboratory of Proteomics, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, 100850, Beijing, China
| | - Taoling Zeng
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Wanjun Dai
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Ningyuan Qiu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Mingfeng Xu
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Yikai Qiao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Lang Ke
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Jiayi Zhao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Xinyu Cao
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Qi Lin
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Xiao Lei Chen
- Cancer Research Center of Xiamen University, 361102, Xiamen, Fujian, China
- School of Medicine, Xiamen University, 361102, Fujian, China
| | - Liping Xie
- School of Medicine, Xiamen University, 361102, Fujian, China
| | - Zhong Ouyang
- Department of Breast Surgery, The First Affiliated Hospital of Xiamen University, 361003, Xiamen, Fujian, China
| | - Jujiang Guo
- Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China
| | - Liangkai Zheng
- Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China
| | - Chao Ma
- Medical School of Chinese PLA, 100853, Beijing, China
| | - Shiying Guo
- GemPharmatech Co., Ltd., 210000, Nanjing, Jiangsu, China
| | - Kangmei Chen
- Department of Clinical Laboratory, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, 510120, Guangzhou, China
| | - Wei Mo
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China
| | - Guo Fu
- Cancer Research Center of Xiamen University, 361102, Xiamen, Fujian, China.
- School of Medicine, Xiamen University, 361102, Fujian, China.
- Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China.
| | - Tong-Jin Zhao
- Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Zhongshan Hospital, Fudan University, 200438, Shanghai, China.
| | - Hong-Rui Wang
- State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, 361102, Fujian, China.
- Department of Obstetrics and Gynecology, Women and Children's Hospital, School of Medicine, Xiamen University, 361003, Xiamen, Fujian, China.
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Valadan R, Dabiri M, Tehrani M, Hashemi Tabar G, Rafiei A. A cell-based subtractive panning strategy for selection of conformation-specific single-chain variable-fragment (scFv) against dimerization domain of EGFR. J Immunol Methods 2023; 515:113456. [PMID: 36898519 DOI: 10.1016/j.jim.2023.113456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/06/2023] [Accepted: 03/06/2023] [Indexed: 03/12/2023]
Abstract
BACKGROUND AND OBJECTIVE Overexpression of EGFR, a member of the ErbB receptor family, has been observed in several cancers and causes resistance to therapeutic antibodies, such as Herceptin. In this study, we produced a recombinant single-chain variable fragment (scFv) antibody against the EGFR dimerization domain. METHODS The recombinant scFv was generated using a cell-based subtractive panning strategy. Subtractive panning was performed on a genetically engineered, VERO/EGFR, cells as well as a triple-negative breast cancer, MDA-MB-468, cells. Phage cell-ELISA was used to monitor the binding of the selected scFvs to the dimerization domain of EGFR. Inhibition of EGFR and HER2 dimerization by the produced scFvs were finally evaluated using the dimerization inhibition test and the expression of apoptosis-related genes were measured using the quantitative RT-PCR. RESULTS PCR fingerprinting results showed a uniform digestion pattern following the third round of panning that confirmed the success of subtractive panning. Moreover, cell-ELISA validated the reactivity of the produced scFvs to EGFR following stimulation with EGF. Dimerization inhibition test showed the capacity of the scFvs to inhibit EGFR and HER2 dimerization. Investigation of apoptosis-related genes showed that treatment with the scFv antibody caused increased Bax and decreased Bcl2 expression. CONCLUSIONS Directed HER2 targeting was shown to be effective enough to block the functional domain of the cell receptor and its intracellular signaling pathway. The subtractive panning strategy used in this study could control the process of directed selection of specific antibodies against the dimerization domain of EGFR. Selected antibodies might then be functionally tested for antitumor effects in both in vitro and in vivo studies.
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Affiliation(s)
- Reza Valadan
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.; Molecular and Cell Biology Research Center (MCBRC), School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mina Dabiri
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.; Molecular and Cell Biology Research Center (MCBRC), School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Mohsen Tehrani
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.; Molecular and Cell Biology Research Center (MCBRC), School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Gholamreza Hashemi Tabar
- Research Institute of Biotechnology, Ferdowsi University of Mashhad, Mashhad, Iran; Department of Pathobiology, School of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Alireza Rafiei
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran.; Molecular and Cell Biology Research Center (MCBRC), School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran..
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Zubair T, Bandyopadhyay D. Small Molecule EGFR Inhibitors as Anti-Cancer Agents: Discovery, Mechanisms of Action, and Opportunities. Int J Mol Sci 2023; 24:ijms24032651. [PMID: 36768973 PMCID: PMC9916655 DOI: 10.3390/ijms24032651] [Citation(s) in RCA: 67] [Impact Index Per Article: 33.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/21/2023] [Accepted: 01/23/2023] [Indexed: 02/01/2023] Open
Abstract
Epidermal growth factor receptors (EGFRs) are a class of receptor tyrosine kinase that are also called ErbB1 and HER1. EGFR tyrosine kinase activity inhibition is considered a promising therapeutic strategy for the treatment of cancer. Many small-molecule inhibitors of EGFR tyrosine kinase (EGFR-TK), from medicinally privileged molecules to commercial drugs, have been overviewed. Particular attention has been paid to the structure of the molecule and its mechanism of action if reported. Subsequent classification of the molecules under discussion has been carried out. Both natural and synthetic and reversible and irreversible EGFR-tyrosine kinase inhibitors have been discussed. Various types of cancers that are caused by overexpression of the EGFR gene, their possible molecular origins, and their natures have also been counted in this article. Because the EGFR signaling pathway controls the proliferation, growth, survival, and differentiation of cells, and the mutated EGFR gene overproduces EGFR protein, which ultimately causes several types of cancer, proper understanding of the molecular dynamics between the protein structure and its inhibitors will lead to more effective and selective EGFR-TKIs, which in turn will be able to save more lives in the battle against cancer.
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Affiliation(s)
- Tanzida Zubair
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
| | - Debasish Bandyopadhyay
- Department of Chemistry, The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
- School of Earth Environment & Marine Sciences (SEEMS), The University of Texas Rio Grande Valley, 1201 West University Drive, Edinburg, TX 78539, USA
- Correspondence:
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31
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Salman G, Aldujaily E, Jabardi M, Qassid OL. Investigating the clinical significance of EGFR expression using machine learning in a series of Iraqi patients with triple-negative breast cancer. J Med Life 2022; 15:967-978. [PMID: 36188649 PMCID: PMC9514808 DOI: 10.25122/jml-2021-0401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 03/14/2022] [Indexed: 11/05/2022] Open
Abstract
Breast cancer is a heterogeneous disease with a distinct profile of the expression of each tumor. Triple-negative breast cancer (TNBC) is a molecular subtype of breast cancer characterized by an aggressive clinical behavior linked to loss or reduced expression of estrogen, progesterone, and Her2/neu receptors. The study's main objective was to investigate the clinical significance of epidermal growth factor receptor (EGFR) overexpression in a series of Iraqi patients with TNBC. The sectional analytic study involved immunohistochemical analysis of EGFR expression in randomly selected 53 formalin fixed paraffin embedded tissue blocks of TNBC cases out of 127 Iraqi patients with TNBC and correlated expression data with clinicopathological parameters including survival time. Machine learning (statistical tests and principal component analysis (PCA)) was used to predict the outcome of the patients using EGFR expression data together with clinicopathological parameters. EGFR was expressed in approximately 28% of TNBC cases. We estimated the risk of mortality and distant metastasis based on EGFR expression and clinicopathologic factors using the principal component analysis (PCA) model. We found a substantial positive correlation between clinical stage and distant metastasis, clinical stage and death, death and distant metastasis, and death and positive EGFR expression. Overall, EGFR expression was linked to a poor prognosis and increased mortality. A higher risk of distant metastasis and death was associated with an advanced clinical stage of the tumor. Furthermore, the existence of distant metastases increased the risk of death. These findings raise the possibility of using EGFR expression data with other clinicopathological parameters to predict the outcome of patients with TNBC.
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Affiliation(s)
- Gufran Salman
- Department of Basic Science, Faculty of Dentistry, University of Kufa, Kufa, Iraq
| | - Esraa Aldujaily
- Department of Pathology and Forensic Medicine, Faculty of Medicine, University of Kufa, Kufa, Iraq,Corresponding Author: Esraa Aldujaily, Department of Pathology and Forensic Medicine, Faculty of Medicine, University of Kufa, Kufa, Iraq. E-mail:
| | - Mohammed Jabardi
- Department of Computer Science, College of Education, University of Kufa, Kufa, Iraq
| | - Omar Layth Qassid
- Cancer Research Center, University of Leicester, Leicester City, United Kingdom
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Abreu de Oliveira WA, El Laithy Y, Bruna A, Annibali D, Lluis F. Wnt Signaling in the Breast: From Development to Disease. Front Cell Dev Biol 2022; 10:884467. [PMID: 35663403 PMCID: PMC9157790 DOI: 10.3389/fcell.2022.884467] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Accepted: 04/22/2022] [Indexed: 12/11/2022] Open
Abstract
The Wnt cascade is a primordial developmental signaling pathway that plays a myriad of essential functions throughout development and adult homeostasis in virtually all animal species. Aberrant Wnt activity is implicated in embryonic and tissue morphogenesis defects, and several diseases, most notably cancer. The role of Wnt signaling in mammary gland development and breast cancer initiation, maintenance, and progression is far from being completely understood and is rather shrouded in controversy. In this review, we dissect the fundamental role of Wnt signaling in mammary gland development and adult homeostasis and explore how defects in its tightly regulated and intricated molecular network are interlinked with cancer, with a focus on the breast.
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Affiliation(s)
- Willy Antoni Abreu de Oliveira
- Department of Development and Regeneration, Stem Cell Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- *Correspondence: Willy Antoni Abreu de Oliveira, ; Frederic Lluis,
| | - Youssef El Laithy
- Department of Development and Regeneration, Stem Cell Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
| | - Alejandra Bruna
- Centre for Paediatric Oncology Experimental Medicine, Centre for Cancer Evolution, Molecular Pathology Division, London, United Kingdom
| | - Daniela Annibali
- Department of Oncology, Gynecological Oncology Laboratory, Leuven Cancer Institute (LKI), KU Leuven, Leuven, Belgium
- Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, Netherlands
| | - Frederic Lluis
- Department of Development and Regeneration, Stem Cell Institute, Katholieke Universiteit (KU) Leuven, Leuven, Belgium
- *Correspondence: Willy Antoni Abreu de Oliveira, ; Frederic Lluis,
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33
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Wang F, Liu X, He J, Zhang N, Chen L, Tang L, Fan D. Analysis of ERBB4 Variants in Amyotrophic Lateral Sclerosis Within a Chinese Cohort. Front Neurol 2022; 13:865264. [PMID: 35481267 PMCID: PMC9035935 DOI: 10.3389/fneur.2022.865264] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 03/04/2022] [Indexed: 11/13/2022] Open
Abstract
ERBB4 is related to amyotrophic lateral sclerosis (ALS) in patients with a family history and is thought to cause ALS-19. We screened 448 ALS patients, including 364 sporadic ALS (sALS) and 84 familial ALS (fALS) patients with ERBB4 variants, in a Chinese cohort. In total, 12 missense variants were identified in this study. Of these, 3 (p.Arg106His, p.Gln164Pro, and p.Val212Leu) were absent from the in-house healthy control cohort and population databases and predicted to be likely pathogenic. Genetic burden analysis did not reveal an increase in damaging variants of the ERBB4 gene. We considered that most of the missense variants in ERBB4 were not pathogenic, but certain variants, such as p.Arg106His, p.Gln164Pro, and p.Val212Leu, were likely pathogenic. The phenotype of these three patients carrying ERBB4 variants revealed the typical clinical manifestations of ALS without cognitive dysfunction. We concluded that ERBB4 likely pathogenic variants account for ~0.67% of ALS patients in China. It is necessary to interpret the relationship between the disease and variants carefully for ALS patients with ERBB4 gene variants.
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Affiliation(s)
- Fan Wang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
| | - Xiangyi Liu
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
| | - Ji He
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
| | - Nan Zhang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
| | - Lu Chen
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
| | - Lu Tang
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
| | - Dongsheng Fan
- Department of Neurology, Peking University Third Hospital, Beijing, China
- Beijing Municipal Key Laboratory of Biomarker and Translational Research in Neurodegenerative Diseases, Beijing, China
- Key Laboratory for Neuroscience, National Health Commission/Ministry of Education, Peking University, Beijing, China
- *Correspondence: Dongsheng Fan
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SERT Pİ, TÜYLÜ KÜÇÜKKILINÇ ZT. Meme Kanseri Tedavisindeki Güncel Yaklaşımlar. HACETTEPE UNIVERSITY JOURNAL OF THE FACULTY OF PHARMACY 2022. [DOI: 10.52794/hujpharm.959879] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Tang R, Langdon WY, Zhang J. Negative regulation of receptor tyrosine kinases by ubiquitination: Key roles of the Cbl family of E3 ubiquitin ligases. Front Endocrinol (Lausanne) 2022; 13:971162. [PMID: 35966060 PMCID: PMC9365936 DOI: 10.3389/fendo.2022.971162] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Receptor tyrosine kinases (RTKs) serve as transmembrane receptors that participate in a broad spectrum of cellular processes including cellular growth, motility, differentiation, proliferation, and metabolism. Hence, elucidating the regulatory mechanisms of RTKs involved in an assortment of diseases such as cancers attracts increasing interest from researchers. Members of the Cbl family ubiquitin ligases (c-Cbl, Cbl-b and Cbl-c in mammals) have emerged as negative regulators of activated RTKs. Upon activation of RTKs by growth factors, Cbl binds to RTKs via its tyrosine kinase binding (TKB) domain and targets them for ubiquitination, thus facilitating their degradation and negative regulation of RTK signaling. RTKs such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGF), fibroblast growth factor receptor (FGFR) and hepatocyte growth factor receptor (HGFR) undergo ubiquitination upon interaction with Cbl family members. In this review, we summarize the current knowledge related to the negative regulation of RTKs by Cbl family proteins.
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Affiliation(s)
- Rong Tang
- Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China
| | - Wallace Y. Langdon
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Jian Zhang
- Department of Pathology, The University of Iowa, Iowa City, IA, United States
- *Correspondence: Jian Zhang,
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Lucas LM, Dwivedi V, Senfeld JI, Cullum RL, Mill CP, Piazza JT, Bryant IN, Cook LJ, Miller ST, Lott JH, Kelley CM, Knerr EL, Markham JA, Kaufmann DP, Jacobi MA, Shen J, Riese DJ. The Yin and Yang of ERBB4: Tumor Suppressor and Oncoprotein. Pharmacol Rev 2022; 74:18-47. [PMID: 34987087 PMCID: PMC11060329 DOI: 10.1124/pharmrev.121.000381] [Citation(s) in RCA: 36] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/15/2021] [Indexed: 12/11/2022] Open
Abstract
ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, a family that includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are oncoproteins and validated targets for therapeutic intervention in a variety of solid tumors. In contrast, the role that ERBB4 plays in human malignancies is ambiguous. Thus, here we review the literature regarding ERBB4 function in human malignancies. We review the mechanisms of ERBB4 signaling with an emphasis on mechanisms of signaling specificity. In the context of this signaling specificity, we discuss the hypothesis that ERBB4 appears to function as a tumor suppressor protein and as an oncoprotein. Next, we review the literature that describes the role of ERBB4 in tumors of the bladder, liver, prostate, brain, colon, stomach, lung, bone, ovary, thyroid, hematopoietic tissues, pancreas, breast, skin, head, and neck. Whenever possible, we discuss the possibility that ERBB4 mutants function as biomarkers in these tumors. Finally, we discuss the potential roles of ERBB4 mutants in the staging of human tumors and how ERBB4 function may dictate the treatment of human tumors. SIGNIFICANCE STATEMENT: This articles reviews ERBB4 function in the context of the mechanistic model that ERBB4 homodimers function as tumor suppressors, whereas ERBB4-EGFR or ERBB4-ERBB2 heterodimers act as oncogenes. Thus, this review serves as a mechanistic framework for clinicians and scientists to consider the role of ERBB4 and ERBB4 mutants in staging and treating human tumors.
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Affiliation(s)
- Lauren M Lucas
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Vipasha Dwivedi
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jared I Senfeld
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Richard L Cullum
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Christopher P Mill
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - J Tyler Piazza
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Ianthe N Bryant
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Laura J Cook
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - S Tyler Miller
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - James H Lott
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Connor M Kelley
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Elizabeth L Knerr
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jessica A Markham
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - David P Kaufmann
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Megan A Jacobi
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - Jianzhong Shen
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
| | - David J Riese
- Department of Drug Discovery and Development, Harrison School of Pharmacy (L.M.L., V.D., J.I.S., R.L.C., C.P.M., J.T.P., L.J.C., S.T.M., J.H.L., C.M.K., E.L.K., J.A.M., D.P.K., M.A.J., J.S., D.J.R.), and Department of Chemical Engineering, Samuel Ginn College of Engineering (R.L.C.), Auburn University, Auburn, Alabama; The University of Texas M.D. Anderson Cancer Center, Houston, Texas (C.P.M.); Office of the Executive Vice President for Research and Partnerships, Purdue University, West Lafayette, Indiana (I.N.B.); and Cancer Biology and Immunology Program, O'Neal Comprehensive Cancer Center, The University of Alabama at Birmingham, Birmingham, Alabama (D.J.R.)
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Hadjittofi C, Feretis M, Martin J, Harper S, Huguet E. Liver regeneration biology: Implications for liver tumour therapies. World J Clin Oncol 2021; 12:1101-1156. [PMID: 35070734 PMCID: PMC8716989 DOI: 10.5306/wjco.v12.i12.1101] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 11/28/2021] [Indexed: 02/06/2023] Open
Abstract
The liver has remarkable regenerative potential, with the capacity to regenerate after 75% hepatectomy in humans and up to 90% hepatectomy in some rodent models, enabling it to meet the challenge of diverse injury types, including physical trauma, infection, inflammatory processes, direct toxicity, and immunological insults. Current understanding of liver regeneration is based largely on animal research, historically in large animals, and more recently in rodents and zebrafish, which provide powerful genetic manipulation experimental tools. Whilst immensely valuable, these models have limitations in extrapolation to the human situation. In vitro models have evolved from 2-dimensional culture to complex 3 dimensional organoids, but also have shortcomings in replicating the complex hepatic micro-anatomical and physiological milieu. The process of liver regeneration is only partially understood and characterized by layers of complexity. Liver regeneration is triggered and controlled by a multitude of mitogens acting in autocrine, paracrine, and endocrine ways, with much redundancy and cross-talk between biochemical pathways. The regenerative response is variable, involving both hypertrophy and true proliferative hyperplasia, which is itself variable, including both cellular phenotypic fidelity and cellular trans-differentiation, according to the type of injury. Complex interactions occur between parenchymal and non-parenchymal cells, and regeneration is affected by the status of the liver parenchyma, with differences between healthy and diseased liver. Finally, the process of termination of liver regeneration is even less well understood than its triggers. The complexity of liver regeneration biology combined with limited understanding has restricted specific clinical interventions to enhance liver regeneration. Moreover, manipulating the fundamental biochemical pathways involved would require cautious assessment, for fear of unintended consequences. Nevertheless, current knowledge provides guiding principles for strategies to optimise liver regeneration potential.
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Affiliation(s)
- Christopher Hadjittofi
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Michael Feretis
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Jack Martin
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Simon Harper
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
| | - Emmanuel Huguet
- University Department of Surgery, Addenbrookes Hospital, NIHR Comprehensive Biomedical Research and Academic Health Sciences Center, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, United Kingdom
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Choi SH, Won KJ, Lee R, Cho HS, Hwang SH, Nah SY. Wound Healing Effect of Gintonin Involves Lysophosphatidic Acid Receptor/Vascular Endothelial Growth Factor Signaling Pathway in Keratinocytes. Int J Mol Sci 2021; 22:10155. [PMID: 34576317 PMCID: PMC8467330 DOI: 10.3390/ijms221810155] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2021] [Revised: 09/14/2021] [Accepted: 09/17/2021] [Indexed: 12/18/2022] Open
Abstract
Gintonin, a novel compound of ginseng, is a ligand of the lysophosphatidic acid (LPA) receptor. The in vitro and in vivo skin wound healing effects of gintonin remain unknown. Therefore, the objective of this study was to investigate the effects of gintonin on wound healing-linked responses, especially migration and proliferation, in skin keratinocytes HaCaT. In this study, 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay, Boyden chamber migration assay, scratch wound healing assay, and Western blot assay were performed. A tail wound mouse model was used for the in vivo test. Gintonin increased proliferation, migration, and scratch closure in HaCaT cells. It also increased the release of vascular endothelial growth factor (VEGF) in HaCaT cells. However, these increases, induced by gintonin, were markedly blocked by treatment with Ki16425, an LPA inhibitor, PD98059, an ERK inhibitor, 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis (acetoxymethyl ester), a calcium chelator, and U73122, a PLC inhibitor. The VEGF receptor inhibitor axitinib also attenuated gintonin-enhanced HaCaT cell proliferation. Gintonin increased the phosphorylation of AKT and ERK1/2 in HaCaT cells. In addition, gintonin improved tail wound healing in mice. These results indicate that gintonin may promote wound healing through LPA receptor activation and/or VEGF release-mediated downstream signaling pathways. Thus, gintonin could be a beneficial substance to facilitate skin wound healing.
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Affiliation(s)
- Sun-Hye Choi
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea; (S.-H.C.); (R.L.); (H.-S.C.)
| | - Kyung-Jong Won
- Department of Physiology and Medical Science, School of Medicine, Konkuk University, Seoul 05029, Korea;
| | - Rami Lee
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea; (S.-H.C.); (R.L.); (H.-S.C.)
| | - Han-Sung Cho
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea; (S.-H.C.); (R.L.); (H.-S.C.)
| | - Sung-Hee Hwang
- Department of Pharmaceutical Engineering, College of Health Sciences, Sangji University, Wonju 26339, Korea
| | - Seung-Yeol Nah
- Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 05029, Korea; (S.-H.C.); (R.L.); (H.-S.C.)
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Tateyama N, Nanamiya R, Ohishi T, Takei J, Nakamura T, Yanaka M, Hosono H, Saito M, Asano T, Tanaka T, Sano M, Kawada M, Kaneko MK, Kato Y. Defucosylated Anti-Epidermal Growth Factor Receptor Monoclonal Antibody 134-mG 2a-f Exerts Antitumor Activities in Mouse Xenograft Models of Dog Epidermal Growth Factor Receptor-Overexpressed Cells. Monoclon Antib Immunodiagn Immunother 2021; 40:177-183. [PMID: 34424762 DOI: 10.1089/mab.2021.0022] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is a type I transmembrane protein, which is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases. EGFR is a crucial mediator of cell growth and differentiation and forms homodimers or heterodimers with other HER family members to activate downstream signaling cascades. We previously established an anti-human EGFR (hEGFR) monoclonal antibody (mAb), clone EMab-134 (mouse IgG1), by immunizing mice with the ectodomain of hEGFR. In this study, the subclass of EMab-134 was converted from IgG1 to IgG2a (134-mG2a) and further defucosylated (134-mG2a-f) to facilitate antibody-dependent cellular cytotoxicity (ADCC). Although 134-mG2a-f was developed against hEGFR, it was shown to cross-react with dog EGFR (dEGFR) using flow cytometry. The dissociation constant (KD) of 134-mG2a-f against dEGFR-overexpressed CHO-K1 (CHO/dEGFR) cells was determined by flow cytometry to be 3.3 × 10-9 M, indicating that 134-mG2a-f possesses a high binding affinity to dEGFR. Analysis in vitro revealed that 134-mG2a-f contributed to high levels of ADCC and complement-dependent cytotoxicity (CDC) in experiments targeting CHO/dEGFR cells. Furthermore, the in vivo administration of 134-mG2a-f significantly inhibited the development of CHO/dEGFR in comparison with the results observed in response to control mouse IgG. Taken together, the findings of this study demonstrate that 134-mG2a-f could be useful as part of a therapeutic regimen for dEGFR-expressing canine cancers.
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Affiliation(s)
- Nami Tateyama
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Ren Nanamiya
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Japan
| | - Junko Takei
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takuro Nakamura
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Miyuki Yanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hideki Hosono
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masaki Saito
- Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masato Sano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu-shi, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Japan.,Department of Molecular Pharmacology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Wang Z, Chan HW, Gambarotta G, Smith NJ, Purdue BW, Pennisi DJ, Porrello ER, O'Brien SL, Reichelt ME, Thomas WG, Paravicini TM. Stimulation of the four isoforms of receptor tyrosine kinase ErbB4, but not ErbB1, confers cardiomyocyte hypertrophy. J Cell Physiol 2021; 236:8160-8170. [PMID: 34170016 DOI: 10.1002/jcp.30487] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2020] [Revised: 06/03/2021] [Accepted: 06/09/2021] [Indexed: 11/11/2022]
Abstract
Epidermal growth factor (EGF) receptors (ErbB1-ErbB4) promote cardiac development and growth, although the specific EGF ligands and receptor isoforms involved in growth/repair versus pathology remain undefined. We challenged ventricular cardiomyocytes with EGF-like ligands and observed that selective activation of ErbB4 (the receptor for neuregulin 1 [NRG1]), but not ErbB1 (the receptor for EGF, EGFR), stimulated hypertrophy. This lack of direct ErbB1-mediated hypertrophy occurred despite robust activation of extracellular-regulated kinase 1/2 (ERK) and protein kinase B. Hypertrophic responses to NRG1 were unaffected by the tyrosine kinase inhibitor (AG1478) at concentrations that are selective for ErbB1 over ErbB4. NRG1-induced cardiomyocyte enlargement was suppressed by small interfering RNA (siRNA) knockdown of ErbB4 and ErbB2, whereas ERK phosphorylation was only suppressed by ErbB4 siRNA. Four ErbB4 isoforms exist (JM-a/JM-b and CYT-1/CYT-2), generated by alternative splicing, and their expression declines postnatally and following cardiac hypertrophy. Silencing of all four isoforms in cardiomyocytes, using an ErbB4 siRNA, abrogated NRG1-induced hypertrophic promoter/reporter activity, which was rescued by coexpression of knockdown-resistant versions of the ErbB4 isoforms. Thus, ErbB4 confers cardiomyocyte hypertrophy to NRG1, and all four ErbB4 isoforms possess the capacity to mediate this effect.
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Affiliation(s)
- Zhen Wang
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Hsiu-Wen Chan
- School of Public Health, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Giovanna Gambarotta
- Department of Clinical and Biological Sciences, University of Torino, Orbassano, Torino, Italy
| | - Nicola J Smith
- School of Medical Sciences, Faculty of Medicine, The University of New South Wales, Sydney, New South Wales, Australia
| | - Brooke W Purdue
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - David J Pennisi
- Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia
| | - Enzo R Porrello
- Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Shannon L O'Brien
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Melissa E Reichelt
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Walter G Thomas
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Tamara M Paravicini
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,School of Health and Biomedical Sciences, RMIT University, Melbourne, Victoria, Australia
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Silva Rocha F, da Silva Maués JH, Brito Lins Pereira CM, Moreira-Nunes CA, Rodriguez Burbano RM. Analysis of Increased EGFR and IGF-1R Signaling and Its Correlation with Socio-Epidemiological Features and Biological Profile in Breast Cancer Patients: A Study in Northern Brazil. BREAST CANCER (DOVE MEDICAL PRESS) 2021; 13:325-339. [PMID: 34054308 PMCID: PMC8153070 DOI: 10.2147/bctt.s308554] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/02/2021] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Breast cancer (BC) is the second most frequent cancer worldwide. It is known that a subset of BC has amplification, and overexpression of the epidermal growth factor receptor (EGFR) and high expression of the insulin-like growth factor receptor-1 (IGF-1R) are correlated with a favorable prognosis. This study aimed to evaluate the prognostic and predictive values of the EGFR and IGF-1R in tumor samples from patients with BC and their correlation with socio-epidemiological features. PATIENTS AND METHODS We analyzed socio-epidemiological, clinical-pathological data and tumor tissues from 124 patients with BC undergoing treatment, to assess levels of EGFR and IGF-1R mRNA and protein. The predictive performance included the calculation of area-under-the-curve (AUC) to discriminate groups of patients with high and low mRNA expression associated with survival analysis within each molecular group of BC. RESULTS We found a significant expression increase (p <0.001) in EGFR associated with body mass index, angiolymphatic invasion, compromised lymph nodes and follow-up in 58.1% of the triple-negative and HER overexpression tumors. The increase in IGF-IR was significant (p <0.001) in 41.9% of luminal tumors A and B. ROC analysis showed that EGFR had a higher predictive performance (AUC = 0.891) than IGF-1R (AUC = 0.60). The Kaplan-Meier analysis indicated that only the high expression of EGFR was associated with a decreased probability of survival for patients, what did not happen with IGF-1R. CONCLUSION Our results suggest that EGFR and IGF-1R expression patterns associated with the clinical characteristics of patients and biological profile influenced the evolution of BC.
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Affiliation(s)
| | - Jersey Heitor da Silva Maués
- Laboratory of Molecular Biology, Ophir Loyola Hospital, Belém, PA, Brazil
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
| | | | - Caroline Aquino Moreira-Nunes
- Laboratory of Pharmacogenetics, Drug Research and Development Center (NPDM), Federal University of Ceará, Fortaleza, CE, Brazil
| | - Rommel Mário Rodriguez Burbano
- Laboratory of Molecular Biology, Ophir Loyola Hospital, Belém, PA, Brazil
- Laboratory of Human Cytogenetics, Institute of Biological Sciences, Federal University of Pará, Belém, PA, Brazil
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Łuczkowska K, Sokolowska KE, Taryma-Lesniak O, Pastuszak K, Supernat A, Bybjerg-Grauholm J, Hansen LL, Paczkowska E, Wojdacz TK, Machaliński B. Bortezomib induces methylation changes in neuroblastoma cells that appear to play a significant role in resistance development to this compound. Sci Rep 2021; 11:9846. [PMID: 33972578 PMCID: PMC8110815 DOI: 10.1038/s41598-021-89128-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Accepted: 04/21/2021] [Indexed: 12/13/2022] Open
Abstract
The anticancer activity of bortezomib (BTZ) has been increasingly studied in a number of indications and promising results for the use of this treatment have been shown in neuroblastoma. As BTZ treatment is usually administered in cycles, the development of resistance and side effects in patients undergoing therapy with BTZ remains a major challenge for the clinical usage of this compound. Common resistance development also means that certain cells are able to survive BTZ treatment and bypass molecular mechanisms that render BTZ anticancer activity. We studied the methylome of neuroblastoma cells that survived BTZ treatment. Our results indicate that BTZ induces pronounced genome wide methylation changes in cells which recovered from the treatment. Functional analyses of identified methylation changes demonstrated they were involved in key cancer pathology pathways. These changes may allow the cells to bypass the primary anticancer activity of BTZ and develop a treatment resistant and proliferative phenotype. To study whether cells surviving BTZ treatment acquire a proliferative phenotype, we repeatedly treated cells which recovered from the first round of BTZ treatment. The repetitive treatment led to induction of the extraordinary proliferative potential of the cells, that increased with subsequent treatments. As we did not observe similar effects in cells that survived treatment with lenalidomide, and non-treated cells cultured under the same experimental conditions, this phenomenon seems to be BTZ specific. Overall, our results indicate that methylation changes may play major role in the development of BTZ resistance.
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Affiliation(s)
- Karolina Łuczkowska
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111, Szczecin, Poland
| | - Katarzyna Ewa Sokolowska
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Unii Lubelskiej 1, 71-252, Szczecin, Poland
| | - Olga Taryma-Lesniak
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Unii Lubelskiej 1, 71-252, Szczecin, Poland
| | - Krzysztof Pastuszak
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland.,Department of Algorithms and Systems Modelling, Faculty of Electronics, Telecommunications and Informatics, Gdańsk University of Technology, Narutowicza 11/12, 80-233, Gdańsk, Poland
| | - Anna Supernat
- Laboratory of Translational Oncology, Intercollegiate Faculty of Biotechnology, Medical University of Gdańsk, Dębinki 1, 80-211, Gdańsk, Poland
| | - Jonas Bybjerg-Grauholm
- Department for Congenital Disorders, Statens Serum Institut, Artillerivej 5, 2300, København S Copenhagen, Denmark
| | - Lise Lotte Hansen
- Department of Biomedicine, Aarhus University, Hoegh-Guldbergsgade 10, 8000, Aarhus, Denmark
| | - Edyta Paczkowska
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111, Szczecin, Poland
| | - Tomasz K Wojdacz
- Independent Clinical Epigenetics Laboratory, Pomeranian Medical University, Unii Lubelskiej 1, 71-252, Szczecin, Poland. .,Department of Biomedicine, Aarhus University, Hoegh-Guldbergsgade 10, 8000, Aarhus, Denmark. .,Aarhus Institute of Advanced Studies, Hoegh-Guldbergs Gade 6B, 8000, Aarhus, Denmark.
| | - Bogusław Machaliński
- Department of General Pathology, Pomeranian Medical University, Powstańców Wlkp. 72, 70-111, Szczecin, Poland.
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Vashi R, Patel BM, Goyal RK. Keeping abreast about ashwagandha in breast cancer. JOURNAL OF ETHNOPHARMACOLOGY 2021; 269:113759. [PMID: 33359916 DOI: 10.1016/j.jep.2020.113759] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2019] [Revised: 10/29/2020] [Accepted: 12/21/2020] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Ashwagandha has been used as an ayurvedic medicine in the form of 'Rasayana' (as a tonic) even before 3000 BCE in India. As per Ayurveda, it has long been used traditionally for the treatment of inflammation, weakness, impotence, pulmonary tuberculosis. This plant is also beneficial in lumbago and leucorrhea in the female. In the recent past, Withania has shown its anti-cancerous activity in various experimental models. In addition, Withania also possesses many other properties such as anti-oxidant, anti-stress, adaptogenic, and regenerative which will eventually be beneficial and safe in treating cancer patients. AIM OF THE STUDY This review aims to provide experimental evidence along with a deeper insight into molecular mechanisms of Ashwagandha (Withania somnifera (L.) Dunal) through which it acts as a chemotherapeutic agent against different types of breast cancer. MATERIALS AND METHODS Literature searches with the help of electronic online databases (Elsevier, Google Scholar, Scopus, Springer Link, ScienceDirect, ResearchGate, PubMed) were carried out. The timeline for collection of data for the review article was from 2000 to 2019. The plant name was validated from The Plant List (2013). Version 1.1. Published on http://www.theplantlist.org/(accessed 21st March 2020). RESULTS Various forms of Withania somnifera were used and several in vitro, in vivo, and clinical studies were reported by researchers. They found ashwagandha to exhibit anti-apoptotic, anti-metastatic, anti-invasive and anti-inflammatory properties and gave the evidence that ashwagandha has a capability for averting and treating breast cancer. CONCLUSION Various in vitro and in vivo studies suggested Ashwagandha may possess a potential for treating breast cancer, especially ER/PR positive breast cancer and triple-negative breast cancer. A clinical trial has also been conducted in the past that suggested its potential in refining quality of life in breast cancer patients. Studies directed towards molecular pathways have helped in unravelling the key mechanisms of ashwagandha. Future research should be directed towards translational studies involving breast cancer patients. These will reinforce the ancient power of our Ayurvedic medicine.
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Affiliation(s)
- Ruju Vashi
- Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, India.
| | - Bhoomika M Patel
- Institute of Pharmacy, Nirma University, Ahmedabad, 382 481, India.
| | - Ramesh K Goyal
- Delhi Pharmaceutical Sciences Research University, Delhi, India.
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Barakeh DH, Aljelaify R, Bashawri Y, Almutairi A, Alqubaishi F, Alnamnakani M, Almubarak L, Al Naeem A, Almushawah F, Alrashed M, Abedalthagafi M. Landscape of somatic mutations in breast cancer: new opportunities for targeted therapies in Saudi Arabian patients. Oncotarget 2021; 12:686-697. [PMID: 33868589 PMCID: PMC8021026 DOI: 10.18632/oncotarget.27909] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 02/19/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer (BCa) ranks first in incidence rate among cancers in Arab females. The association between genetic polymorphisms in tumor suppressor genes and the risk of BCa has been studied in many ethnic populations with conflicting conclusions while Arab females and Saudi Arabian studies are still lacking. We screened a cohort of Saudi BCa patients by NGS using a bespoke gene panel to clarify the genetic landscape of this population, correlating and assessing genetic findings with clinical outcomes. We identified a total of 263 mutations spanning 51 genes, including several frequently mutated. Among the genes analyzed, the highest mutation rates were found in PIK3CA (12.9%), BRCA2 (11.7%), BRCA1 (10.2%), TP53 (6.0%), MSH2 (3.8%), PMS2 (3.8%), BARD1 (3.8%), MLH1 (3.4%), CDH1 (3.0%), RAD50 (3.0%), MSH6 (3.0%), NF1 (2.6%), in addition to others. We identified multiple common recurrent variants and previously reported mutations. We also identified 46 novel variants in 22 genes that were predicted to have a pathogenic effect. Survival analysis according to the four most common mutations (BRCA1, BRCA2, TP53, and PIK3CA) showed reduced survival in BRCA1 and BRCA2-mutant patients compared to total patients. Moreover, BRCA2 was demonstrated as an independent predictor of reduced survival using independent Cox proportional hazard models. We reveal the landscape of the mutations associated with BCa in Saudi women, highlighting the importance of routine genetic sequencing in implementation of precision therapies in KSA.
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Affiliation(s)
- Duna H Barakeh
- Department of Pathology, King Saud University Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Rasha Aljelaify
- Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia
| | - Yara Bashawri
- Department of Biostatistics, Research Centre, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Amal Almutairi
- Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia
| | - Fatimah Alqubaishi
- Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia
| | - Mohammed Alnamnakani
- Department of Pathology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Latifa Almubarak
- Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia
| | - Abdulrahman Al Naeem
- Department of Radiology, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - Fatema Almushawah
- Department of Surgery, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
| | - May Alrashed
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Saud University, Riyadh, Kingdom of Saudi Arabia.,Chair of Medical and Molecular Genetics Research, King Saud University, Riyadh, Kingdom of Saudi Arabia
| | - Malak Abedalthagafi
- Genomics Research Department, Saudi Human Genome Project, King Fahad Medical City and King Abdulaziz City for Science and Technology, Riyadh, Kingdom of Saudi Arabia
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45
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Tilak M, Holborn J, New LA, Lalonde J, Jones N. Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme. Int J Mol Sci 2021; 22:1831. [PMID: 33673213 PMCID: PMC7918566 DOI: 10.3390/ijms22041831] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2020] [Revised: 02/08/2021] [Accepted: 02/10/2021] [Indexed: 12/20/2022] Open
Abstract
Glioblastoma multiforme (GBM) is amongst the deadliest of human cancers, with a median survival rate of just over one year following diagnosis. Characterized by rapid proliferation and diffuse infiltration into the brain, GBM is notoriously difficult to treat, with tumor cells showing limited response to existing therapies and eventually developing resistance to these interventions. As such, there is intense interest in better understanding the molecular alterations in GBM to guide the development of more efficient targeted therapies. GBM tumors can be classified into several molecular subtypes which have distinct genetic signatures, and they show aberrant activation of numerous signal transduction pathways, particularly those connected to receptor tyrosine kinases (RTKs) which control glioma cell growth, survival, migration, invasion, and angiogenesis. There are also non-canonical modes of RTK signaling found in GBM, which involve G-protein-coupled receptors and calcium channels. This review uses The Cancer Genome Atlas (TCGA) GBM dataset in combination with a data-mining approach to summarize disease characteristics, with a focus on select molecular pathways that drive GBM pathogenesis. We also present a unique genomic survey of RTKs that are frequently altered in GBM subtypes, as well as catalog the GBM disease association scores for all RTKs. Lastly, we discuss current RTK targeted therapies and highlight emerging directions in GBM research.
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Affiliation(s)
| | | | | | | | - Nina Jones
- Department of Molecular and Cellular Biology, University of Guelph, Guelph, ON N1G 2W1, Canada; (M.T.); (J.H.); (L.A.N.); (J.L.)
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Samatiwat P, Tabtimmai L, Suphakun P, Jiwacharoenchai N, Toviwek B, Kukongviriyapan V, Gleeson MP, Choowongkomon K. The Effect of the EGFR - Targeting Compound 3-[(4-Phenylpyrimidin-2-yl) Amino] Benzene-1-Sulfonamide (13f) against Cholangiocarcinoma Cell Lines. Asian Pac J Cancer Prev 2021; 22:381-390. [PMID: 33639651 PMCID: PMC8190356 DOI: 10.31557/apjcp.2021.22.2.381] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2020] [Accepted: 02/05/2021] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE Cholangiocarcinoma (CCA) is a noxious malignancy of epithelium of the bile duct with a low response rate to chemotherapy. The epidermal growth factor receptor (EGFR) signaling pathway is implicated in the development of cancerous cells, especially CCA. In this study, we report detailed biological profiling of 13f identified from our earlier hit expansion studies. The aim of this work was to expand our understanding of 13f via more detailed investigations of its mechanism of action against KKU-100, KKU-452 and KKU-M156 CCA cells, as well as in comparison to the EGFR inhibitor Gefitinib and non-specific chemotherapeutic agents such as Cisplatin. METHODS Inhibiting EGFR-Kinase, cytotoxicity, clonogenic assay, wound healing and apoptosis were performed. Levels of total expression of EGFR and EGFR phosphorylation proteins were detected. RESULTS 13f was confirmed as an inhibitor of EGFR with an IC50 value against the tyrosine kinase of EGFR of 22 nM and IC50 values for 48 h incubation period were 1.3 ± 1.9, 1.5 ± 0.4 and 1.7 ± 1.1 µM of KKU-100, KKU-452 and KKU-M156, respectively through dose- and time-dependent induction of early apoptosis of CCA cells. The compound also suppressed the clonogenic ability of KKU-100 and KKU-M156 cells stronger than Gefitinib, while potently inhibiting EGF-stimulated CCA cell migratory activity in KKU-452 cells. It was observed that under normal conditions EGFR was activated in CCA cells. EGF-stimulated basal expression of EGFR in KKU-452 cells was suppressed following 13f treatment, which was significantly greater than that of the marketed EGFR inhibitor Gefitinib. CONCLUSION In summary, our study showed that 13f has potent anti-cancer activities including antiproliferation, clonogenic ability and migration through the modulation of EGFR signaling pathway in CCA for the first time. The compound represents an interesting starting point as a potential chemotherapeutic agent in ongoing efforts to improve response rate in CCA patients.
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Affiliation(s)
- Papavee Samatiwat
- Department of Pharmacology, Faculty of Medicine, Srinakharinwirot University, Bangkok, 10110, Thailand.
| | - Lueacha Tabtimmai
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
| | - Prapasri Suphakun
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
| | - Nattanan Jiwacharoenchai
- Genetic Engineering Interdisciplinary Program, Graduate School, Kasetsart University, 10900, Thailand.
| | | | - Veerapol Kukongviriyapan
- Department of Pharmacology, Faculty of Medicine, Khon Kaen University, Khon Kaen, 40002, Thailand.
- Cholangiocarcinoma Research Institute, Khon Kaen University, Khon Kaen, 40002, Thailand.
| | - M. Paul Gleeson
- Department of Biomedical Engineering, Faculty of Engineering, King Mongkut’s Institute of Technology Ladkrabang, Bangkok. Thailand.
| | - Kiattawee Choowongkomon
- Department of Biochemistry, Kasetsart University, Bangkok, 10900, Thailand.
- Center for Advanced Studies in Nanotechnology for Chemical, Food and Agricultural Industries, KU Institute for Advanced Studies, Kasetsart University, Bangkok 10900, Thailand.
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Sabbah DA, Hajjo R, Sweidan K. Review on Epidermal Growth Factor Receptor (EGFR) Structure, Signaling Pathways, Interactions, and Recent Updates of EGFR Inhibitors. Curr Top Med Chem 2021; 20:815-834. [PMID: 32124699 DOI: 10.2174/1568026620666200303123102] [Citation(s) in RCA: 282] [Impact Index Per Article: 70.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 11/21/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022]
Abstract
The epidermal growth factor receptor (EGFR) belongs to the ERBB family of tyrosine kinase receptors. EGFR signaling cascade is a key regulator in cell proliferation, differentiation, division, survival, and cancer development. In this review, the EGFR structure and its mutations, signaling pathway, ligand binding and EGFR dimerization, EGF/EGFR interaction, and the progress in the development of EGFR inhibitors have been explored.
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Affiliation(s)
- Dima A Sabbah
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Rima Hajjo
- Department of Pharmacy, Faculty of Pharmacy, Al-Zaytoonah University of Jordan, P.O. Box 130, Amman 11733, Jordan
| | - Kamal Sweidan
- Department of Chemistry, The University of Jordan, Amman 11942, Jordan
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48
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Fischer A, Wolf I, Fuchs H, Masilamani AP, Wolf P. Pseudomonas Exotoxin A Based Toxins Targeting Epidermal Growth Factor Receptor for the Treatment of Prostate Cancer. Toxins (Basel) 2020; 12:E753. [PMID: 33260619 PMCID: PMC7761469 DOI: 10.3390/toxins12120753] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Revised: 11/24/2020] [Accepted: 11/26/2020] [Indexed: 12/16/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) was found to be a valuable target on prostate cancer (PCa) cells. However, EGFR inhibitors mostly failed in clinical studies with patients suffering from PCa. We therefore tested the targeted toxins EGF-PE40 and EGF-PE24mut consisting of the natural ligand EGF as binding domain and PE40, the natural toxin domain of Pseudomonas Exotoxin A, or PE24mut, the de-immunized variant thereof, as toxin domains. Both targeted toxins were expressed in the periplasm of E.coli and evoked an inhibition of protein biosynthesis in EGFR-expressing PCa cells. Concentration- and time-dependent killing of PCa cells was found with IC50 values after 48 and 72 h in the low nanomolar or picomolar range based on the induction of apoptosis. EGF-PE24mut was found to be about 11- to 120-fold less toxic than EGF-PE40. Both targeted toxins were more than 600 to 140,000-fold more cytotoxic than the EGFR inhibitor erlotinib. Due to their high and specific cytotoxicity, the EGF-based targeted toxins EGF-PE40 and EGF-PE24mut represent promising candidates for the future treatment of PCa.
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Affiliation(s)
- Alexandra Fischer
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.F.); (I.W.); (A.P.M.)
- Department of Urology, Antibody-Based Diagnostics and Therapies, Medical Center—University of Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany
| | - Isis Wolf
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.F.); (I.W.); (A.P.M.)
- Department of Urology, Antibody-Based Diagnostics and Therapies, Medical Center—University of Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany
| | - Hendrik Fuchs
- Institute of Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Charité—Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 13353 Berlin, Germany;
| | - Anie Priscilla Masilamani
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.F.); (I.W.); (A.P.M.)
- Department of Urology, Antibody-Based Diagnostics and Therapies, Medical Center—University of Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany
| | - Philipp Wolf
- Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany; (A.F.); (I.W.); (A.P.M.)
- Department of Urology, Antibody-Based Diagnostics and Therapies, Medical Center—University of Freiburg, Breisacher Str. 66, 79106 Freiburg, Germany
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49
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Sreedurgalakshmi K, Srikar R, Rajkumari R. CRISPR-Cas deployment in non-small cell lung cancer for target screening, validations, and discoveries. Cancer Gene Ther 2020; 28:566-580. [PMID: 33191402 DOI: 10.1038/s41417-020-00256-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Revised: 10/14/2020] [Accepted: 10/29/2020] [Indexed: 12/24/2022]
Abstract
Continued advancements in CRISPR-Cas systems have accelerated genome research. Use of CRISPR-Cas in cancer research has been of great interest that is resulting in development of orthogonal methods for drug target validations and discovery of new therapeutic targets through genome-wide screens of cancer cells. CRISPR-based screens have also revealed several new cancer drivers through alterations in tumor suppressor genes (TSGs) and oncogenes inducing resistance to targeted therapies via activation of alternate signaling pathways. Given such dynamic status of cancer, we review the application of CRISPR-Cas in non-small cell lung cancer (NSCLC) for development of mutant models, drug screening, target validation, novel target discoveries, and other emerging potential applications. In addition, CRISPR-based approach for development of novel anticancer combination therapies is also discussed in this review.
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Affiliation(s)
- K Sreedurgalakshmi
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu, India.,Division of Biosimilars and Gene Therapy, R&D, Levim Biotech LLP, Chennai, Tamilnadu, India
| | - R Srikar
- Division of Biosimilars and Gene Therapy, R&D, Levim Biotech LLP, Chennai, Tamilnadu, India.
| | - Reena Rajkumari
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamilnadu, India.
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50
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Pan PC, Magge RS. Mechanisms of EGFR Resistance in Glioblastoma. Int J Mol Sci 2020; 21:E8471. [PMID: 33187135 PMCID: PMC7696540 DOI: 10.3390/ijms21228471] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Revised: 11/04/2020] [Accepted: 11/09/2020] [Indexed: 12/13/2022] Open
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite numerous efforts to target epidermal growth factor receptor (EGFR), commonly dysregulated in GBM, approaches directed against EGFR have not achieved the same degree of success as seen in other tumor types, particularly as compared to non-small cell lung cancer (NSCLC). EGFR alterations in glioblastoma lie primarily in the extracellular domain, unlike the kinase domain alterations seen in NSCLC. Small molecule inhibitors are difficult to develop for the extracellular domain. Monoclonal antibodies can be developed to target the extracellular domain but must contend with the blood brain barrier (BBB). We review the role of EGFR in GBM, the history of trialed treatments, and the potential paths forward to target the pathway that may have greater success.
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Affiliation(s)
- Peter C. Pan
- Division of Neuro-Oncology, NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Rajiv S. Magge
- Division of Neuro-Oncology, NewYork-Presbyterian/Weill Cornell Medicine, New York, NY 10021, USA;
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