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1
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Garrett JT, Tendler S, Feroz W, Kilroy MK, Yu H. Emerging importance of HER3 in tumorigenesis and cancer therapy. Nat Rev Clin Oncol 2025:10.1038/s41571-025-01008-y. [PMID: 40087402 DOI: 10.1038/s41571-025-01008-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/24/2025] [Indexed: 03/17/2025]
Abstract
HER3 is a member of the HER/ErbB family of receptor tyrosine kinases, together with EGFR (HER1), HER2 and HER4. Despite having only weak intrinsic kinase activity, HER3 can contribute to oncogenic signalling via ligand-induced heterodimerization with other HER family members. Evidence indicates that HER3 is altered or aberrantly expressed across a variety of tumour types and can be associated with poor clinical outcomes. Whereas anticancer agents targeting EGFR and HER2 have been approved for decades, no drug targeting HER3 had been approved until very recently. Initial targeting of HER3 with monoclonal antibodies as single agents or in combination with other therapeutics produced disappointing clinical results. Subsequently, efforts have been made to target HER3 with novel agents such as antibody-drug conjugates and bispecific antibodies, with promising efficacy observed in several trials encompassing various tumour types. In December 2024, the HER3 × HER2 bispecific antibody zenocutuzumab was granted FDA Accelerated Approval for the treatment of non-small-cell lung cancers or pancreatic cancers harbouring fusions involving NRG1, the gene encoding the high-affinity HER3 ligand neuregulin 1. In this Review, we provide an essential guide to HER3 signalling and oncogenesis, HER3 expression in cancer and its prognostic implications, oncogenic HER3 somatic mutations as well as rare NRG1 fusions that might depend on HER3 signalling, and the roles of HER3 in resistance to cancer therapies. We also highlight efforts to target HER3 with diverse therapeutic strategies and the potential interplay between HER3 and the antitumour immune response.
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Affiliation(s)
- Joan T Garrett
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA.
| | - Salomon Tendler
- Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wasim Feroz
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Mary Kate Kilroy
- Division of Pharmaceutical Sciences, James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH, USA
| | - Helena Yu
- Department of Medicine, Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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2
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Arai T, Hayashi E, Maeda S, Matsubara T, Fujii H, Shinohara K, Sogabe A, Wainai S, Tanaka D, Ono Y, Ono Y, Yoshikai M, Sorimachi Y, Kok CYY, Shimoda M, Tanaka M, Kawada N, Goda N. Liver-derived Neuregulin1α stimulates compensatory pancreatic β cell hyperplasia in insulin resistance. Nat Commun 2025; 16:1950. [PMID: 40082404 PMCID: PMC11906622 DOI: 10.1038/s41467-025-57167-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Accepted: 02/13/2025] [Indexed: 03/16/2025] Open
Abstract
Compensatory pancreatic islet hyperplasia is an adaptive response to increased systemic insulin demand, although factors meditating this response remain poorly understood. Here, we show that a liver-derived secreted protein, Neuregulin1α, promotes compensatory proliferation of pancreatic β cells in type 2 diabetes. Liver Neuregulin1α expression and serum Neuregulin1α levels increase in male mice fed an obesity-inducing diet. Male mice lacking either Neuregulin1 in liver or its receptor, ErbB3, in β cells deteriorate systemic glucose disposal due to impaired β cell expansion with reduced insulin secretion when fed the obesity-inducing diet. Mechanistically, Neuregulin1α activates ERBB2/3-ERK signaling to stimulate β cell proliferation without altering glucose-stimulated insulin secretion potential. In patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and obesity but without type 2 diabetes serum Neuregulin1α levels increase, while in patient with MASLD and type 2 diabetes show markedly reduced levels of Neuregulin1α. These results suggest that Neuregulin1α serves as a hepatokine that can expand functional β cell mass in type 2 diabetes.
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Affiliation(s)
- Takatomo Arai
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Eriko Hayashi
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Sumie Maeda
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Tsutomu Matsubara
- Department of Anatomy and Regenerative Biology, Osaka Metropolitan University, Osaka, Japan
| | - Hideki Fujii
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Koya Shinohara
- Department of Pancreatic Islet Cell Transplantation, National Center for Global Health and Medicine, Tokyo, Japan
| | - Arisu Sogabe
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Sadatomo Wainai
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Daishi Tanaka
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Yutaro Ono
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Yumika Ono
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Minami Yoshikai
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan
| | - Yuriko Sorimachi
- Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Cindy Yuet-Yin Kok
- Neuroscience Research Australia, Sydney, NSW, Australia
- Discipline of Medicine, Randwick Clinical Campus, University of New South Wales, Sydney, NSW, Australia
| | - Masayuki Shimoda
- Department of Pancreatic Islet Cell Transplantation, National Center for Global Health and Medicine, Tokyo, Japan
| | - Minoru Tanaka
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Nobuhito Goda
- Department of Life Science and Medical Bioscience, Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan.
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Chen Z, He R, Huang S, Zhou Y, Zhang Z, Wang Z, Ding K. Discovery of CZY43 as a new small-molecule degrader of pseudokinase HER3. Eur J Med Chem 2025; 285:117258. [PMID: 39818014 DOI: 10.1016/j.ejmech.2025.117258] [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: 11/10/2024] [Revised: 12/24/2024] [Accepted: 01/06/2025] [Indexed: 01/18/2025]
Abstract
The pseudokinase HER3 emerges as a promising anti-cancer target, especially for HER2-driven breast cancer and EGFR-mediated non-small cell lung cancer. However, it is challenging to target HER3 by ATP-competitive small molecules because HER3 is catalytically impaired. Herein, we report the discovery of a series of HER3 degraders by connecting a HER3 binder bosutinib with a hydrophobic tag adamantane. The optimal compound CZY43 effectively induced HER3 degradation in dose- and time-dependent manners in breast cancer SKBR3 cells. Mechanistic studies revealed compound CZY43 to induce HER3 degradation via autophagy. Importantly, compound CZY43 potently inhibited HER3-dependent signaling, cancer cell growth and cell adhesion, and was more potent than bosutinib. This study further suggested that HER3 can be modulated by small-molecule degraders, and compound CZY43 can serve as a lead compound for further optimization.
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Affiliation(s)
- Zhiyuan Chen
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd, Shanghai, 200032, China; University of Chinese Academy of Sciences, No. 1 Yanxihu Road Huairou District, Beijing, 101408, China
| | - Rui He
- 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, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China
| | - Shengjie Huang
- 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, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China
| | - Yang Zhou
- 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, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China
| | - Zhang Zhang
- 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, College of Pharmacy, Jinan University, 855 Xingye Avenue East, Guangzhou, 511400, China
| | - Zhen Wang
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd, Shanghai, 200032, China; Ningbo Zhongke Creation Center of New Materials, Ningbo, 315000, China
| | - Ke Ding
- State Key Laboratory of Chemical Biology, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, #345 Lingling Rd, Shanghai, 200032, China.
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4
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Gao L, Zhang Y, Feng M, Shen M, Yang L, Wei B, Zhou Y, Zhang Z. HER3: Updates and current biology function, targeted therapy and pathologic detecting methods. Life Sci 2024; 357:123087. [PMID: 39366553 DOI: 10.1016/j.lfs.2024.123087] [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: 07/20/2024] [Revised: 09/18/2024] [Accepted: 09/28/2024] [Indexed: 10/06/2024]
Abstract
Being a member of the EGFR tyrosine kinase family, HER3 has been shown to be overexpressed in a number of cancers, including breast cancer (BC). The kinase activity of HER3 is extremely low, and it forms heterodimers with partners, HER2 in particular, that promote biological processes like cell migration, survival, and proliferation by activating downstream carcinogenic signaling pathways. The overexpression of HER3 is also directly linked to tumor invasion, metastasis, and a poor prognosis. Despite the relatively low expression of HER3 compared to EGFR and HER2, a lot of targeted drugs are making their way into clinical trials and seem to have a bright further. This review aims to summarize the relationship between HER3 overexpression, mutations, and carcinogenicity and drug resistance, starting from the unique structure and kinase activity of HER3. Simultaneously, numerous approaches to HER3 targeted therapy are enumerated, and the clinical detection methods for HER3 that are commonly employed in pathology are sorted and contrasted to offer physicians a range of options. We think that a better knowledge of the mechanisms underlying HER3 in tumors and the advancement of targeted HER3 therapy will contribute to an improved prognosis for cancer patients and an increase in the efficacy of anticancer therapies.
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Affiliation(s)
- Leyi Gao
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China
| | - Yu Zhang
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China
| | - Mengna Feng
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China
| | - Mengjia Shen
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China
| | - Libo Yang
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China
| | - Bing Wei
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China
| | - Yongjie Zhou
- Laboratory of Liver Transplantation, West China Hospital, Sichuan University, Chengdu 610041, China.
| | - Zhang Zhang
- Department of Pathology, West China Hospital, Sichuan University, No.37, Guo Xue Xiang, Chengdu 610041, Sichuan, China.
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5
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Rodrigues Toledo C, Tantawy AA, Lima Fuscaldi L, Malavolta L, de Aguiar Ferreira C. EGFR- and Integrin α Vβ 3-Targeting Peptides as Potential Radiometal-Labeled Radiopharmaceuticals for Cancer Theranostics. Int J Mol Sci 2024; 25:8553. [PMID: 39126121 PMCID: PMC11313252 DOI: 10.3390/ijms25158553] [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: 06/26/2024] [Revised: 07/29/2024] [Accepted: 07/30/2024] [Indexed: 08/12/2024] Open
Abstract
The burgeoning field of cancer theranostics has witnessed advancements through the development of targeted molecular agents, particularly peptides. These agents exploit the overexpression or mutations of specific receptors, such as the Epidermal Growth Factor receptor (EGFR) and αVβ3 integrin, which are pivotal in tumor growth, angiogenesis, and metastasis. Despite the extensive research into and promising outcomes associated with antibody-based therapies, peptides offer a compelling alternative due to their smaller size, ease of modification, and rapid bioavailability, factors which potentially enhance tumor penetration and reduce systemic toxicity. However, the application of peptides in clinical settings has challenges. Their lower binding affinity and rapid clearance from the bloodstream compared to antibodies often limit their therapeutic efficacy and diagnostic accuracy. This overview sets the stage for a comprehensive review of the current research landscape as it relates to EGFR- and integrin αVβ3-targeting peptides. We aim to delve into their synthesis, radiolabeling techniques, and preclinical and clinical evaluations, highlighting their potential and limitations in cancer theranostics. This review not only synthesizes the extant literature to outline the advancements in peptide-based agents targeting EGFR and integrin αVβ3 but also identifies critical gaps that could inform future research directions. By addressing these gaps, we contribute to the broader discourse on enhancing the diagnostic precision and therapeutic outcomes of cancer treatments.
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Affiliation(s)
- Cibele Rodrigues Toledo
- The Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USA; (C.R.T.); (A.A.T.)
| | - Ahmed A. Tantawy
- The Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USA; (C.R.T.); (A.A.T.)
- Comparative Medicine and Integrative Biology, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA
| | - Leonardo Lima Fuscaldi
- Department of Physiological Sciences, Santa Casa de Sao Paulo School of Medical Sciences, São Paulo 01221-020, Brazil; (L.L.F.); (L.M.)
| | - Luciana Malavolta
- Department of Physiological Sciences, Santa Casa de Sao Paulo School of Medical Sciences, São Paulo 01221-020, Brazil; (L.L.F.); (L.M.)
| | - Carolina de Aguiar Ferreira
- The Institute for Quantitative Health Science & Engineering, Michigan State University, East Lansing, MI 48824, USA; (C.R.T.); (A.A.T.)
- Department of Radiology, Michigan State University, East Lansing, MI 48824, USA
- Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI 48824, USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
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6
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Kucharczyk T, Nicoś M, Kucharczyk M, Kalinka E. NRG1 Gene Fusions-What Promise Remains Behind These Rare Genetic Alterations? A Comprehensive Review of Biology, Diagnostic Approaches, and Clinical Implications. Cancers (Basel) 2024; 16:2766. [PMID: 39123493 PMCID: PMC11311641 DOI: 10.3390/cancers16152766] [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: 07/11/2024] [Revised: 08/01/2024] [Accepted: 08/03/2024] [Indexed: 08/12/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) presents a variety of druggable genetic alterations that revolutionized the treatment approaches. However, identifying new alterations may broaden the group of patients benefitting from such novel treatment options. Recently, the interest focused on the neuregulin-1 gene (NRG1), whose fusions may have become a potential predictive factor. To date, the occurrence of NRG1 fusions has been considered a negative prognostic marker in NSCLC treatment; however, many premises remain behind the targetability of signaling pathways affected by the NRG1 gene. The role of NRG1 fusions in ErbB-mediated cell proliferation especially seems to be considered as a main target of treatment. Hence, NSCLC patients harboring NRG1 fusions may benefit from targeted therapies such as pan-HER family inhibitors, which have shown efficacy in previous studies in various cancers, and anti-HER monoclonal antibodies. Considering the increased interest in the NRG1 gene as a potential clinical target, in the following review, we highlight its biology, as well as the potential clinical implications that were evaluated in clinics or remained under consideration in clinical trials.
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Affiliation(s)
- Tomasz Kucharczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-059 Lublin, Poland;
| | - Marek Kucharczyk
- Department of Zoology and Nature Conservation, Institute of Biology, Maria Curie-Sklodowska University in Lublin, 20-033 Lublin, Poland;
| | - Ewa Kalinka
- Oncology Clinic, Institute of the Polish Mother’s Health Center in Lodz, 93-338 Lodz, Poland;
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7
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Koivu MKA, Chakroborty D, Airenne TT, Johnson MS, Kurppa KJ, Elenius K. Trans-activating mutations of the pseudokinase ERBB3. Oncogene 2024; 43:2253-2265. [PMID: 38806620 PMCID: PMC11245391 DOI: 10.1038/s41388-024-03070-9] [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: 02/09/2023] [Revised: 05/15/2024] [Accepted: 05/20/2024] [Indexed: 05/30/2024]
Abstract
Genetic changes in the ERBB family of receptor tyrosine kinases serve as oncogenic driver events and predictive biomarkers for ERBB inhibitor drugs. ERBB3 is a pseudokinase member of the family that, although lacking a fully active kinase domain, is well known for its potent signaling activity as a heterodimeric complex with ERBB2. Previous studies have identified few transforming ERBB3 mutations while the great majority of the hundreds of different somatic ERBB3 variants observed in different cancer types remain of unknown significance. Here, we describe an unbiased functional genetics screen of the transforming potential of thousands of ERBB3 mutations in parallel. The screen based on a previously described iSCREAM (in vitro screen of activating mutations) platform, and addressing ERBB3 pseudokinase signaling in a context of ERBB3/ERBB2 heterodimers, identified 18 hit mutations. Validation experiments in Ba/F3, NIH 3T3, and MCF10A cell backgrounds demonstrated the presence of both previously known and unknown transforming ERBB3 missense mutations functioning either as single variants or in cis as a pairwise combination. Drug sensitivity assays with trastuzumab, pertuzumab and neratinib indicated actionability of the transforming ERBB3 variants.
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Affiliation(s)
- Marika K A Koivu
- Institute of Biomedicine, and Medicity Research Laboratories, University of Turku, Turku, 20520, Finland
- Turku Doctoral Programme of Molecular Medicine, Turku, 20520, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, 20520, Finland
| | - Deepankar Chakroborty
- Institute of Biomedicine, and Medicity Research Laboratories, University of Turku, Turku, 20520, Finland
- Turku Doctoral Programme of Molecular Medicine, Turku, 20520, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, 20520, Finland
| | - Tomi T Airenne
- Structural Bioinformatics Laboratory and InFLAMES Research Flagship Center, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520, Turku, Finland
| | - Mark S Johnson
- Structural Bioinformatics Laboratory and InFLAMES Research Flagship Center, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, 20520, Turku, Finland
| | - Kari J Kurppa
- Institute of Biomedicine, and Medicity Research Laboratories, University of Turku, Turku, 20520, Finland
| | - Klaus Elenius
- Institute of Biomedicine, and Medicity Research Laboratories, University of Turku, Turku, 20520, Finland.
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, 20520, Finland.
- Department of Oncology, Turku University Hospital, Turku, 20521, Finland.
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8
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Zhou YT, Chu JH, Zhao SH, Li GL, Fu ZY, Zhang SJ, Gao XH, Ma W, Shen K, Gao Y, Li W, Yin YM, Zhao C. Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities. Acta Pharmacol Sin 2024; 45:1287-1304. [PMID: 38360930 PMCID: PMC11130324 DOI: 10.1038/s41401-024-01232-9] [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: 08/09/2023] [Accepted: 01/23/2024] [Indexed: 02/17/2024]
Abstract
HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.
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Affiliation(s)
- Ya-Ting Zhou
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Jia-Hui Chu
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shu-Han Zhao
- Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Ge-Li Li
- Gusu School, Nanjing Medical University, Suzhou, 215000, China
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Zi-Yi Fu
- Department of Breast Disease Research Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Su-Jie Zhang
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Xue-Hu Gao
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
- Jiangsu Hengrui Medicine Co. Ltd, Shanghai, 200245, China
| | - Wen Ma
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China
| | - Kai Shen
- Jiangsu Hengrui Medicine Co. Ltd, Shanghai, 200245, China
| | - Yuan Gao
- QSPMed Technologies, Nanjing, 210000, China
| | - Wei Li
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yong-Mei Yin
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Chen Zhao
- Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
- School of Pharmacy, Nanjing Medical University, Nanjing, 211166, China.
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9
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Chakraborty J, Chakraborty S, Chakraborty S, Narayan MN. Entanglement of MAPK pathways with gene expression and its omnipresence in the etiology for cancer and neurodegenerative disorders. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2023; 1866:194988. [PMID: 37739217 DOI: 10.1016/j.bbagrm.2023.194988] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 09/14/2023] [Accepted: 09/18/2023] [Indexed: 09/24/2023]
Abstract
Mitogen Activated Protein Kinase (MAPK) is one of the most well characterized cellular signaling pathways that controls fundamental cellular processes including proliferation, differentiation, and apoptosis. These cellular functions are consequences of transcription of regulatory genes that are influenced and regulated by the MAP-Kinase signaling cascade. MAP kinase components such as Receptor Tyrosine Kinases (RTKs) sense external cues or ligands and transmit these signals via multiple protein complexes such as RAS-RAF, MEK, and ERKs and eventually modulate the transcription factors inside the nucleus to induce transcription and other regulatory functions. Aberrant activation, dysregulation of this signaling pathway, and genetic alterations in any of these components results in the developmental disorders, cancer, and neurodegenerative disorders. Over the years, the MAPK pathway has been a prime pharmacological target, to treat complex human disorders that are genetically linked such as cancer, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The current review re-visits the mechanism of MAPK pathways in gene expression regulation. Further, a current update on the progress of the mechanistic understanding of MAPK components is discussed from a disease perspective.
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Affiliation(s)
- Joydeep Chakraborty
- Institute for Advancing Health through Agriculture, Texas A&M Agrilife, College Station, TX, USA
| | - Sayan Chakraborty
- Department of Anesthesiology, Weill Cornell School of Medicine, New York, USA
| | - Sohag Chakraborty
- Human Oncology & Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, USA
| | - Mahesh N Narayan
- Department of Chemistry and Biochemistry, University of Texas, El Paso, TX, USA.
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10
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Shah AA, Kumar N, Mohinder Singh Bedi P, Akhtar S. Molecular modeling, dynamic simulation, and metabolic reactivity studies of quinazoline derivatives to investigate their anti-angiogenic potential by targeting wild EGFR wt and mutant EGFR T790M receptor tyrosine kinases. J Biomol Struct Dyn 2023; 42:13130-13152. [PMID: 37921704 DOI: 10.1080/07391102.2023.2274974] [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: 07/25/2023] [Accepted: 10/18/2023] [Indexed: 11/04/2023]
Abstract
Non-small cell lung cancer, head and neck cancer, glioblastoma, and various other cancer types often demonstrate persistent elevation in EGFR tyrosine kinase activity due to acquired mutations in its kinase domain. Any alteration in the EGFR is responsible for triggering the upregulation of tumor angiogenic pathways, such as the PI3k-AKT-mTOR pathway, MAPK-ERK pathway and PLC-Ƴ pathway, which are critically involved in promoting tumor angiogenesis in cancer cells. The emergence of frequently occurring EGFR kinase domain mutations (L858R/T790M/C797S) that confer resistance to approved therapeutic agents has presented a significant challenge for researchers aiming to develop effective and well-tolerated treatments against tumor angiogenesis. In this study, we directed our efforts towards the rational design and development of novel quinazoline derivatives with the potential to act as antagonists against both wild-type and mutant EGFR. Our approach encompasing the application of advanced drug design strategies, including structure-based virtual screening, molecular docking, molecular dynamics, metabolic reactivity and cardiotoxicity prediction studies led to the identification of two prominent lead compounds: QU648, for EGFRwt inhibition and QU351, for EGFRmt antagonism. The computed binding energies of selected leads and their molecular dynamics simulations exhibited enhanced conformational stability of QU648 and QU351 when compared to standard drugs Erlotinib and Afatinib. Notably, the lead compounds also demonstrated promising pharmacokinetic properties, metabolic reactivity, and cardiotoxicity profiles. Collectively, the outcomes of our study provide compelling evidence supporting the potential of QU648 and QU351 as prominent anti-angiogenic agents, effectively inhibiting EGFR activity across various cancer types harboring diverse EGFR mutations.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
| | - Nitish Kumar
- Department of Pharmaceutical Sciences, Guru Nanak Dev University, Amritsar, India
| | | | - Salman Akhtar
- Department of Bioengineering, Integral University, Lucknow, India
- Novel Global Community Educational Foundation, Hebersham, Australia
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11
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Drury F, Grover M, Hintze M, Saunders J, Fasseas MK, Constantinou C, Barkoulas M. A PAX6-regulated receptor tyrosine kinase pairs with a pseudokinase to activate immune defense upon oomycete recognition in Caenorhabditis elegans. Proc Natl Acad Sci U S A 2023; 120:e2300587120. [PMID: 37725647 PMCID: PMC10523662 DOI: 10.1073/pnas.2300587120] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Accepted: 08/21/2023] [Indexed: 09/21/2023] Open
Abstract
Oomycetes were recently discovered as natural pathogens of Caenorhabditis elegans, and pathogen recognition alone was shown to be sufficient to activate a protective transcriptional program characterized by the expression of multiple chitinase-like (chil) genes. However, the molecular mechanisms underlying oomycete recognition in animals remain fully unknown. We performed here a forward genetic screen to uncover regulators of chil gene induction and found several independent loss-of-function alleles of old-1 and flor-1, which encode receptor tyrosine kinases belonging to the C. elegans-specific KIN-16 family. We report that OLD-1 and FLOR-1 are both necessary for mounting the immune response and act in the epidermis. FLOR-1 is a pseudokinase that acts downstream of the active kinase OLD-1 and regulates OLD-1 levels at the plasma membrane. Interestingly, the old-1 locus is adjacent to the chil genes in the C. elegans genome, thereby revealing a genetic cluster important for oomycete resistance. Furthermore, we demonstrate that old-1 expression at the anterior side of the epidermis is regulated by the VAB-3/PAX6 transcription factor, well known for its role in visual system development in other animals. Taken together, our study reveals both conserved and species-specific factors shaping the activation and spatial characteristics of the immune response to oomycete recognition.
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Affiliation(s)
- Florence Drury
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
| | - Manish Grover
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
| | - Mark Hintze
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
| | - Jonathan Saunders
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
| | - Michael K. Fasseas
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
| | - Charis Constantinou
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
| | - Michalis Barkoulas
- Department of Life Sciences, Imperial College, LondonSW7 2AZ, United Kingdom
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12
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Qiu J, Liu Q, Li P, Jiang Q, Chen W, Li D, Li G, Shan G. Ligand-Directed Photodegradation of Interacting Proteins: Oxidative HER2/HER3 Heterodimer Degradation with a Lapatinib-Derived Photosensitizer. J Med Chem 2023; 66:10265-10272. [PMID: 37421416 DOI: 10.1021/acs.jmedchem.3c00252] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2023]
Abstract
In this work, we described a photocatalytic approach, termed ligand-directed photodegradation of interacting proteins (LDPIP), for efficient protein-protein heterodimer degradation. This LDPIP approach utilizes a combination of a photosensitizing protein ligand and appropriate light and molecular oxygen to induce oxidative damage to the ligand-binding protein as well as its interacting protein partner. As a showcase study, a photosensitizing HER2 ligand HER-PS-I was rationally designed based on the FDA-approved HER2 inhibitor lapatinib to efficiently degrade HER2 together with its interacting protein partner HER3, which is thought to induce HER2-targeted therapy resistance and difficult to target by small molecules. HER-PS-I exhibited excellent anticancer activity against drug-resistant MDA-MB-453 cells and its three-dimensional multicellular spheroids. We hope that this LDPIP approach would find more applications in degrading proteins that are thought undruggable or difficult to drug.
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Affiliation(s)
- Jingru Qiu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Qinghong Liu
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Peixia Li
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Qiaoyun Jiang
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Weijia Chen
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
| | - Donghai Li
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China
| | - Guiling Li
- Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P. R. China
| | - Gang Shan
- Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong Province 250012, P. R. China
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13
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Pal AA, Benman W, Mumford TR, Huang Z, Chow BY, Bugaj LJ. Optogenetic clustering and membrane translocation of the BcLOV4 photoreceptor. Proc Natl Acad Sci U S A 2023; 120:e2221615120. [PMID: 37527339 PMCID: PMC10410727 DOI: 10.1073/pnas.2221615120] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Accepted: 06/25/2023] [Indexed: 08/03/2023] Open
Abstract
Optogenetic tools respond to light through one of a small number of behaviors including allosteric changes, dimerization, clustering, or membrane translocation. Here, we describe a new class of optogenetic actuator that simultaneously clusters and translocates to the plasma membrane in response to blue light. We demonstrate that dual translocation and clustering of the BcLOV4 photoreceptor can be harnessed for novel single-component optogenetic tools, including for control of the entire family of epidermal growth factor receptor (ErbB1-4) tyrosine kinases. We further find that clustering and membrane translocation are mechanistically linked. Stronger clustering increased the magnitude of translocation and downstream signaling, increased sensitivity to light by ~threefold-to-fourfold, and decreased the expression levels needed for strong signal activation. Thus light-induced clustering of BcLOV4 provides a strategy to generate a new class of optogenetic tools and to enhance existing ones.
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Affiliation(s)
- Ayush Aditya Pal
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
| | - William Benman
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
| | - Thomas R. Mumford
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
| | - Zikang Huang
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
| | - Brian Y. Chow
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
| | - Lukasz J. Bugaj
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA19104
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA19104
- Institute of Regenerative Medicine, University of Pennsylvania, Philadelphia, PA19104
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14
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Li Y, Liu Z, Zhao Y, Yang J, Xiao TS, Conlon RA, Wang Z. PD-L1 expression is regulated by ATP-binding of the ERBB3 pseudokinase domain. Genes Dis 2023; 10:1702-1713. [PMID: 37397533 PMCID: PMC10311099 DOI: 10.1016/j.gendis.2022.11.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2022] [Revised: 11/02/2022] [Accepted: 11/05/2022] [Indexed: 12/13/2022] Open
Abstract
How PD-L1 expression is regulated in cancer is poorly understood. Here, we report that the ATP-binding activity of ERBB3 pseudokinase regulates PD-L1 gene expression in colorectal cancers (CRCs). ERBB3 is one of the four members of the EGF receptor family, all with protein tyrosine kinase domains. ERBB3 is a pseudokinase with a high binding affinity to ATP. We showed that ERBB3 ATP-binding inactivation mutant reduces tumorigenicity in genetically engineered mouse models and impairs xenograft tumor growth of CRC cell lines. The ERBB3 ATP-binding mutant cells dramatically reduce IFN-γ-induced PD-L1 expression. Mechanistically, ERBB3 regulates IFN-γ-induced PD-L1 expression through the IRS1-PI3K-PDK1-RSK-CREB signaling axis. CREB is the transcription factor that regulates PD-L1 gene expression in CRC cells. Knockin of a tumor-derived ERBB3 mutation located in the kinase domain sensitizes mouse colon cancers to anti-PD1 antibody therapy, suggesting that ERBB3 mutations could be predictive biomarkers for tumors amenable to immune checkpoint therapy.
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Affiliation(s)
- Yamu Li
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Zhonghua Liu
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Yiqing Zhao
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Jie Yang
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
- Department of Physiology and Biophysics, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Tsan Sam Xiao
- Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Ronald A. Conlon
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
| | - Zhenghe Wang
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
- Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
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15
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Abstract
The epidermal growth factor (EGF) system has allowed chemists, biologists, and clinicians to improve our understanding of cell production and cancer therapy. The discovery of EGF led to the recognition of cell surface receptors capable of controlling the proliferation and survival of cells. The detailed structures of the EGF-like ligand and the responses of their receptors (EGFR-family) has revealed the conformational and aggregation changes whereby ligands activate the intracellular kinase domains. Biophysical analysis has revealed the preformed clustering of different EGFR-family members and the processes which occur on ligand binding. Understanding these receptor activation processes and the consequential cytoplasmic signaling has allowed the development of inhibitors which are revolutionizing cancer therapy. This Review describes the recent progress in our understanding of the activation of the EGFR-family, the effects of signaling from the EGFR-family on cell proliferation, and the targeting of the EGFR-family in cancer treatment.
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Affiliation(s)
- Antony W Burgess
- Honorary Laboratory Head, Personalized Oncology Division, WEHI, Parkville3050, Australia.,Professor Emeritus, Departments of Medical Biology and Surgery (Royal Melbourne Hospital), University of Melbourne, Melbourne3052, Australia.,The Brain Cancer Centre at WEHI, Parkville3052, Australia
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16
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Burgess AW. Regulation of Signaling from the Epidermal Growth Factor Family. THE JOURNAL OF PHYSICAL CHEMISTRY C 2022. [DOI: 10.1021/acs.jpcc.2c04156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Affiliation(s)
- Antony W. Burgess
- Honorary Laboratory Head, Personalized Oncology Division, WEHI, Parkville 3050, Australia
- Professor Emeritus, Departments of Medical Biology and Surgery (Royal Melbourne Hospital), University of Melbourne, Melbourne 3052, Australia
- The Brain Cancer Centre at WEHI, Parkville 3052, Australia
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17
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Yang X, Chen Y, Li M, Zhu W. ERBB3 methylation and immune infiltration in tumor microenvironment of cervical cancer. Sci Rep 2022; 12:8112. [PMID: 35581263 PMCID: PMC9114106 DOI: 10.1038/s41598-022-11415-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2021] [Accepted: 04/22/2022] [Indexed: 11/09/2022] Open
Abstract
ERBB3, a member of the ERBB family of receptor tyrosine kinases, plays an important role in cancer, despite its lack of intrinsic carcinogenic mechanism of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Research on bioinformatics methods through multi-omics, this work proves that ERBB3 gene mutation, methylation modification have extensive regulatory mechanisms on the CESC microenvironment. We found that ERBB3 is involved in carcinogenesis of cervical cancer and is not associated with its prognosis. The carcinogenic mechanism is mainly related to the suppression of the immune system between tumor infiltrating lymphocytes (TILs) and the methylation of the RNA level. Our study indicated ERBB3 is more likely to be a carcinogenic factor than a key prognostic factor for cervical cancer. Methylation of ERBB3 may work as a checkpoint immunotherapy target in CESC, DNA methylation modification of the 4480 base pair downstream of ERBB3 transcription initiation site was the highest.
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Affiliation(s)
- Xiaoyue Yang
- Department of Obstetrics and Gynecology, Affiliated Hospital of Jiangsu University, Jiefang Road 438, Zhenjiang, 212001, Jiangsu, China.,Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Sanxiang Road 1055, Suzhou, 215000, Jiangsu, China
| | - Ying Chen
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Sanxiang Road 1055, Suzhou, 215000, Jiangsu, China
| | - Mei Li
- Department of Pathology, Affiliated Hospital of Jiangsu University, Jiefang Road 438, Zhenjiang, 212001, Jiangsu, China.
| | - Weipei Zhu
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Soochow University, Sanxiang Road 1055, Suzhou, 215000, Jiangsu, China.
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18
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Trenker R, Diwanji D, Verba KA, Jura N. An effective strategy for ligand-mediated pulldown of the HER2/HER3/NRG1β heterocomplex and cryo-EM structure determination at low sample concentrations. Methods Enzymol 2022; 667:633-662. [PMID: 35525557 PMCID: PMC9288110 DOI: 10.1016/bs.mie.2022.03.049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Obtaining high-resolution structures of Receptor Tyrosine Kinases that visualize extracellular, transmembrane and intracellular kinase regions simultaneously is an eagerly pursued but still unmet challenge of structural biology. The Human Epidermal Growth Factor Receptor 3 (HER3) that has a catalytically inactive kinase domain (pseudokinase) forms a potent signaling complex upon binding of growth factor neuregulin 1β (NRG1β) and upon dimerization with a close homolog, the HER2 receptor. The HER2/HER3/NRG1β complex is often referred to as an oncogenic driver in breast cancer and is an attractive target for anti-cancer therapies. After overcoming significant hurdles in isolating sufficient amounts of the HER2/HER3/NRG1β complex for structural studies by cryo-electron microscopy (cryo-EM), we recently obtained the first high-resolution structures of the extracellular portion of this complex. Here we describe a step-by-step protocol for obtaining a stable and homogenous HER2/HER3/NRG1β complex for structural studies and our recommendation for collecting and processing cryo-EM data for this sample. We also show improved EM density for the transmembrane and kinase domains of the receptors, which continue to evade structural determination at high resolution. The discussed strategies are tunable and applicable to other membrane receptor complexes.
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Affiliation(s)
- Raphael Trenker
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, United States
| | - Devan Diwanji
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, United States; Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, United States
| | - Kliment A Verba
- Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, United States; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, United States.
| | - Natalia Jura
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, United States; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, United States.
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19
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Diwanji D, Trenker R, Jura N, Verba KA. Efficient expression, purification, and visualization by cryo-EM of unliganded near full-length HER3. Methods Enzymol 2022; 667:611-632. [PMID: 35525556 PMCID: PMC9288109 DOI: 10.1016/bs.mie.2022.03.048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
Biochemical analyses of membrane receptor kinases have been limited by challenges in obtaining sufficient homogeneous receptor samples for downstream structural and biophysical characterization. Here, we report a suite of methods for the efficient expression, purification, and visualization by cryo-electron microscopy (cryo-EM) of near full-length Human Epidermal Growth Factor Receptor 3 (HER3), a receptor tyrosine pseudokinase, in the unliganded state. Through transient mammalian cell expression, a two-step purification with detergent exchange into lauryl maltose neopentyl glycol (LMNG), and freezing devoid of background detergent micelle, we obtained ~6Å reconstructions of the ~60kDa fully-glycosylated unliganded extracellular domain of HER3 from just 30mL of suspension culture. The reconstructions reveal previously unappreciated extracellular domain dynamics and glycosylation sites.
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Affiliation(s)
- Devan Diwanji
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, United States; Medical Scientist Training Program, University of California San Francisco, San Francisco, CA, United States
| | - Raphael Trenker
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, United States
| | - Natalia Jura
- Cardiovascular Research Institute, University of California San Francisco, San Francisco, CA, United States; Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, United States; Department of Cellular and Molecular Pharmacology, University of California San Francisco, San Francisco, CA, United States.
| | - Kliment A Verba
- Quantitative Biosciences Institute (QBI), University of California San Francisco, San Francisco, CA, United States; Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA, United States.
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20
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The HER family as therapeutic targets in colorectal cancer. Crit Rev Oncol Hematol 2022; 174:103681. [PMID: 35462030 DOI: 10.1016/j.critrevonc.2022.103681] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2021] [Revised: 03/30/2022] [Accepted: 04/07/2022] [Indexed: 12/23/2022] Open
Abstract
The human epidermal growth factor receptor (HER, ErbB) family has four members, epidermal growth factor receptor (EGFR), HER2, HER3, and HER4. Although distinct in ligands and functions, all of the HER family members are receptor tyrosine kinases playing important roles in the pathogenesis of cancers. In the era of precision medicine, the HER family is one of the most important and successful cancer therapeutic targets, hallmarked by the approval of anti-EGFR therapies for the treatment of colorectal cancer and non-small cell lung cancer, and anti-HER2 therapies for the treatment of breast cancer and gastric cancer. This review briefly discusses how HER family members were discovered, their functions and roles in cancer, and most importantly, the developmental history and recent updates of therapies targeting HER family members, with colorectal cancer as a focus. We also discussed the patient selection and drug resistance to anti-EGFR therapies in the treatment of colorectal cancer.
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21
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Campbell MR, Ruiz-Saenz A, Peterson E, Agnew C, Ayaz P, Garfinkle S, Littlefield P, Steri V, Oeffinger J, Sampang M, Shan Y, Shaw DE, Jura N, Moasser MM. Targetable HER3 functions driving tumorigenic signaling in HER2-amplified cancers. Cell Rep 2022; 38:110291. [PMID: 35108525 PMCID: PMC8889928 DOI: 10.1016/j.celrep.2021.110291] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2020] [Revised: 08/30/2021] [Accepted: 12/29/2021] [Indexed: 12/26/2022] Open
Abstract
Effective inactivation of the HER2-HER3 tumor driver has remained elusive because of the challenging attributes of the pseudokinase HER3. We report a structure-function study of constitutive HER2-HER3 signaling to identify opportunities for targeting. The allosteric activation of the HER2 kinase domain (KD) by the HER3 KD is required for tumorigenic signaling and can potentially be targeted by allosteric inhibitors. ATP binding within the catalytically inactive HER3 KD provides structural rigidity that is important for signaling, but this is mimicked, not opposed, by small molecule ATP analogs, reported here in a bosutinib-bound crystal structure. Mutational disruption of ATP binding and molecular dynamics simulation of the apo KD of HER3 identify a conformational coupling of the ATP pocket with a hydrophobic AP-2 pocket, analogous to EGFR, that is critical for tumorigenic signaling and feasible for targeting. The value of these potential target sites is confirmed in tumor growth assays using gene replacement techniques.
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Affiliation(s)
- Marcia R Campbell
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ana Ruiz-Saenz
- Departments of Cell Biology & Medical Oncology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Elliott Peterson
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Christopher Agnew
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Pelin Ayaz
- D. E. Shaw Research, New York, NY 10036, USA
| | | | - Peter Littlefield
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Veronica Steri
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Julie Oeffinger
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Maryjo Sampang
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Yibing Shan
- D. E. Shaw Research, New York, NY 10036, USA
| | - David E Shaw
- D. E. Shaw Research, New York, NY 10036, USA; Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
| | - Natalia Jura
- Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Mark M Moasser
- Department of Medicine, University of California, San Francisco, San Francisco, CA 94143, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
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22
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Valle‑Mendiola A, Bustos‑Rodríguez R, Domínguez‑Melendez V, Zerecero‑Carreón O, Gutiérrez‑Hoya A, Weiss‑Steider B, Soto‑cruz I. Mutations in the helix αC of the catalytic domain from the EGFR affect its activity in cervical cancer cell lines. Oncol Lett 2022; 23:71. [PMID: 35069880 PMCID: PMC8756430 DOI: 10.3892/ol.2022.13191] [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: 09/15/2021] [Accepted: 11/26/2021] [Indexed: 11/06/2022] Open
Abstract
The EGFR is a protein that belongs to the ErbB family of tyrosine kinase receptors. The EGFR is often overexpressed in human carcinomas. Amplification of the EGFR gene and mutations in the EGFR tyrosine kinase domain occur in patients with cancer. In cervical cancer, the expression level of the EGFR protein appears to directly associate with human papillomavirus infection. Our previous research demonstrated that in the cervical cancer cell lines, CALO and INBL, the EGFR is non-phosphorylated. The aim of the current study was to analyze the catalytic activity of the isolated EGFR and the presence of mutations in the control region αC. Catalytic activity was assessed by a universal in vitro kinase assay using polyGluTyr as a substrate, and the proteins were visualized by western blotting. For mutation analysis, DNA from CALO and INBL cell lines was isolated, and PCR was used to amplify the exons corresponding to the helix αC in the EGFR. The PCR products were visualized by agarose gel electrophoresis. The bands were isolated using a Zymoclean Gel DNA Recovery kit and directly sequenced. The EGFR, which was isolated and analyzed using the in vitro kinase assay, had catalytic activity. The receptor contained some mutations in the helix αC of the catalytic domain in both cell lines. The observed changes in the amino acid sequence may induce a different spatial arrangement and, therefore, a different conformation, which may confer different activities to this receptor. Thus, it was concluded that non-phosphorylated EGFR has catalytic activity, and it bears some amino acid changes in the helix αC of the catalytic domain in the CALO and INBL cells. These results suggest that the EGFR may function as an activator of other ErbB family receptors in these cervical cancer cells.
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Affiliation(s)
- Arturo Valle‑Mendiola
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Ricardo Bustos‑Rodríguez
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | | | - Octavio Zerecero‑Carreón
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Adriana Gutiérrez‑Hoya
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Benny Weiss‑Steider
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
| | - Isabel Soto‑cruz
- Molecular Oncology Laboratory, Cell Differentiation and Cancer Research Unit, UMIEZ Campus II, FES Zaragoza, National University of Mexico, Iztapalapa, Mexico City 09230, Mexico
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23
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Chakroborty D, Ojala VK, Knittle AM, Drexler J, Tamirat MZ, Ruzicka R, Bosch K, Woertl J, Schmittner S, Elo LL, Johnson MS, Kurppa KJ, Solca F, Elenius K. An Unbiased Functional Genetics Screen Identifies Rare Activating ERBB4 Mutations. CANCER RESEARCH COMMUNICATIONS 2022; 2:10-27. [PMID: 36860695 PMCID: PMC9973412 DOI: 10.1158/2767-9764.crc-21-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 10/04/2021] [Accepted: 12/21/2021] [Indexed: 06/18/2023]
Abstract
UNLABELLED Despite the relatively high frequency of somatic ERBB4 mutations in various cancer types, only a few activating ERBB4 mutations have been characterized, primarily due to lack of mutational hotspots in the ERBB4 gene. Here, we utilized our previously published pipeline, an in vitro screen for activating mutations, to perform an unbiased functional screen to identify potential activating ERBB4 mutations from a randomly mutated ERBB4 expression library. Ten potentially activating ERBB4 mutations were identified and subjected to validation by functional and structural analyses. Two of the 10 ERBB4 mutants, E715K and R687K, demonstrated hyperactivity in all tested cell models and promoted cellular growth under two-dimensional and three-dimensional culture conditions. ERBB4 E715K also promoted tumor growth in in vivo Ba/F3 cell mouse allografts. Importantly, all tested ERBB4 mutants were sensitive to the pan-ERBB tyrosine kinase inhibitors afatinib, neratinib, and dacomitinib. Our data indicate that rare ERBB4 mutations are potential candidates for ERBB4-targeted therapy with pan-ERBB inhibitors. STATEMENT OF SIGNIFICANCE ERBB4 is a member of the ERBB family of oncogenes that is frequently mutated in different cancer types but the functional impact of its somatic mutations remains unknown. Here, we have analyzed the function of over 8,000 randomly mutated ERBB4 variants in an unbiased functional genetics screen. The data indicate the presence of rare activating ERBB4 mutations in cancer, with potential to be targeted with clinically approved pan-ERBB inhibitors.
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Affiliation(s)
- Deepankar Chakroborty
- Institute of Biomedicine, University of Turku, Turku, Finland
- Medicity Research Laboratories, University of Turku, Turku, Finland
- Turku Doctoral Programme of Molecular Medicine, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Veera K. Ojala
- Institute of Biomedicine, University of Turku, Turku, Finland
- Medicity Research Laboratories, University of Turku, Turku, Finland
- Turku Doctoral Programme of Molecular Medicine, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Anna M. Knittle
- Institute of Biomedicine, University of Turku, Turku, Finland
| | | | - Mahlet Z. Tamirat
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
- Graduate School of Åbo Akademi University (Informational and Structural Biology Doctoral Network), Turku, Finland
| | | | - Karin Bosch
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | | | | | - Laura L. Elo
- Institute of Biomedicine, University of Turku, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Mark S. Johnson
- Structural Bioinformatics Laboratory, Biochemistry, Faculty of Science and Engineering, Åbo Akademi University, Turku, Finland
- InFLAMES Research Flagship Center, Åbo Akademi University, Turku, Finland
| | - Kari J. Kurppa
- Institute of Biomedicine, University of Turku, Turku, Finland
- Medicity Research Laboratories, University of Turku, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
| | - Flavio Solca
- Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Klaus Elenius
- Institute of Biomedicine, University of Turku, Turku, Finland
- Medicity Research Laboratories, University of Turku, Turku, Finland
- Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland
- Department of Oncology, Turku University Hospital, Turku, Finland
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24
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Trombetta D, Sparaneo A, Fabrizio FP, Di Micco CM, Rossi A, Muscarella LA. NRG1 and NRG2 fusions in non-small cell lung cancer (NSCLC): seven years between lights and shadows. Expert Opin Ther Targets 2021; 25:865-875. [PMID: 34706602 DOI: 10.1080/14728222.2021.1999927] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Fusions in neuregulin 1 (NRG1) and neuregulin 2 (NRG2) genes are molecular features of non-small cell lung cancer (NSCLC). These rearrangements enhance ectopic expression of the NRG/ErbB receptor-ligand and induce the triggering of downstream pathways. Evidence suggests the involvement of the NRG1/ErbB3 axis deregulation in the progression and treatment resistance of NSCLC cancer (NSCLC) and that NRG1 fusions are prognostic/predictive markers for targeted therapy. AREAS COVERED Biological and prognostic/predictive value of NRG1 and NRG2 fusions in NSCLC and their related cellular pathways are described and discussed. Publications in English language, peer-reviewed, high-quality international journals were identified on PubMed, as well as scientific official sites were used to update the international clinical trials progress. EXPERT OPINION NRG1 and NRG2 fusions should be considered as novel markers for biological therapy targeting ErbB2/ErbB3. There is evidence for the involvement of the NRG1/ErbB3 axis deregulation in cancer stem cell phenotype, tumor progression, and resistance to NSCLC therapy. Neuregulin fusions are very complex, hence many question marks must be tackled before translating these molecular lesions into clinical practice. Biology, and aggressiveness of the NRG1 and NRG2 fusions warrant further investigations.
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Affiliation(s)
- Domenico Trombetta
- Laboratory of Oncology, Fondazione Irccs Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Angelo Sparaneo
- Laboratory of Oncology, Fondazione Irccs Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Federico Pio Fabrizio
- Laboratory of Oncology, Fondazione Irccs Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Concetta Martina Di Micco
- Unit of Oncology, Fondazione Irccs Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Antonio Rossi
- Unit of Oncology, Fondazione Irccs Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy
| | - Lucia Anna Muscarella
- Laboratory of Oncology, Fondazione Irccs Casa Sollievo Della Sofferenza Hospital, San Giovanni Rotondo, Italy
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25
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Umemoto K, Sunakawa Y. The potential targeted drugs for fusion genes including NRG1 in pancreatic cancer. Crit Rev Oncol Hematol 2021; 166:103465. [PMID: 34454058 DOI: 10.1016/j.critrevonc.2021.103465] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Revised: 08/22/2021] [Accepted: 08/24/2021] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer (PC) remains an incurable disease with few treatment options Recently, promising targets have been identified and novel therapeutic drugs are currently under development in KRAS wild-type PC. It has been reported that KRAS wild-type PC has the genomic alterations such as oncogenic derivers and kinase fusions. NRG1 fusion, which encodes the neuregulin 1 and is the main ligands for ERRB3, has been identified in approximately half of younger patients with PC with KRAS wild-type tumors by RNA sequencing. There are several promising targeted therapies for NRG1 fusion-positive tumors, such as EGFR-tyrosine kinase inhibitor, HER3, HER2 antibodies. BRAF, NTRK, and ALK fusion are also potentially actionable alterations in KRAS wild-type PC and novel therapies targeting certain aberrations have shown activity in clinical trials.
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Affiliation(s)
- Kumiko Umemoto
- Department of Clinical Oncology, St. Marianna University School of Medicine, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St. Marianna University School of Medicine, Japan.
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26
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Eliseev IE, Ukrainskaya VM, Yudenko AN, Mikushina AD, Shmakov SV, Afremova AI, Ekimova VM, Vronskaia AA, Knyazev NA, Shamova OV. Targeting ErbB3 Receptor in Cancer with Inhibitory Antibodies from Llama. Biomedicines 2021; 9:biomedicines9091106. [PMID: 34572289 PMCID: PMC8467012 DOI: 10.3390/biomedicines9091106] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 01/05/2023] Open
Abstract
The human ErbB3 receptor confers resistance to the pharmacological inhibition of EGFR and HER2 receptor tyrosine kinases in cancer, which makes it an important therapeutic target. Several anti-ErbB3 monoclonal antibodies that are currently being developed are all classical immunoglobulins. We took a different approach and discovered a group of novel heavy-chain antibodies targeting the extracellular domain of ErbB3 via a phage display of an antibody library from immunized llamas. We first produced three selected single-domain antibodies, named BCD090-P1, BCD090-M2, and BCD090-M456, in E. coli, as SUMO fusions that yielded up to 180 mg of recombinant protein per liter of culture. Then, we studied folding, aggregation, and disulfide bond formation, and showed their ultimate stability with half-denaturation of the strongest candidate, BCD090-P1, occurring in 8 M of urea. In surface plasmon resonance experiments, two most potent antibodies, BCD090-P1 and BCD090-M2, bound the extracellular domain of ErbB3 with 1.6 nM and 15 nM affinities for the monovalent interaction, respectively. The receptor binding was demonstrated by immunofluorescent confocal microscopy on four different ErbB3+ cancer cell lines. We observed that BCD090-P1 and BCD090-M2 bind noncompetitively to two distinct epitopes on the receptor. Both antibodies inhibited the ErbB3-driven proliferation of MCF-7 breast adenocarcinoma cells and HER2-overexpressing SK-BR-3 cells, with the EC50 in the range of 0.1–25 μg/mL. BCD090-M2 directly blocks ligand binding, whereas BCD090-P1 does not compete with the ligand and presumably acts through a distinct allosteric mechanism. We anticipate that these llama antibodies can be used to engineer new biparatopic anti-ErbB3 or bispecific anti-ErbB2/3 antibodies.
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Affiliation(s)
- Igor E. Eliseev
- Laboratory of Renewable Energy Sources, Alferov University, St. Petersburg 194021, Russia; (A.D.M.); (S.V.S.); (A.A.V.)
- Center for Personalized Medicine, FSBSI Institute of Experimental Medicine, St. Petersburg 197376, Russia;
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia;
- Correspondence:
| | - Valeria M. Ukrainskaya
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow 117997, Russia;
| | - Anna N. Yudenko
- Research Center for Molecular Mechanisms of Aging and Age-Related Diseases, Moscow Institute of Physics and Technology, Dolgoprudny 141700, Russia;
| | - Anna D. Mikushina
- Laboratory of Renewable Energy Sources, Alferov University, St. Petersburg 194021, Russia; (A.D.M.); (S.V.S.); (A.A.V.)
| | - Stanislav V. Shmakov
- Laboratory of Renewable Energy Sources, Alferov University, St. Petersburg 194021, Russia; (A.D.M.); (S.V.S.); (A.A.V.)
| | | | | | - Anna A. Vronskaia
- Laboratory of Renewable Energy Sources, Alferov University, St. Petersburg 194021, Russia; (A.D.M.); (S.V.S.); (A.A.V.)
| | - Nickolay A. Knyazev
- Saint-Petersburg Clinical Scientific and Practical Center for Specialized Types of Medical Care (Oncological), St. Petersburg 197758, Russia;
| | - Olga V. Shamova
- Center for Personalized Medicine, FSBSI Institute of Experimental Medicine, St. Petersburg 197376, Russia;
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27
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McInerney-Leo AM, Chew HY, Inglis PL, Leo PJ, Joseph SR, Cooper CL, Okano S, Hassall T, Anderson L, Bowman RV, Gattas M, Harris JE, Marshall MS, Shaw JG, Wheeler L, Yang IA, Brown MA, Fong KM, Simpson F, Duncan EL. Germline ERBB3 mutation in familial non-small cell lung carcinoma: Expanding ErbB's role in oncogenesis. Hum Mol Genet 2021; 30:2393-2401. [PMID: 34274969 PMCID: PMC8643496 DOI: 10.1093/hmg/ddab172] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 06/12/2021] [Accepted: 06/21/2021] [Indexed: 11/22/2022] Open
Abstract
Lung cancer is the commonest cause of cancer deaths worldwide. Although strongly associated with smoking, predisposition to lung cancer is also heritable, with multiple common risk variants identified. Rarely, dominantly inherited non-small-cell lung cancer (NSCLC) has been reported due to somatic mutations in EGFR/ErbB1 and ERBB2. Germline exome sequencing was performed in a multi-generation family with autosomal dominant NSCLC, including an affected child. Tumour samples were also sequenced. Full-length wild-type (wtErbB3) and mutant ERBB3 (mutErbB3) constructs were transfected into HeLa cells. Protein expression, stability, and subcellular localization were assessed, and cellular proliferation, pAkt/Akt and pERK levels determined. A novel germline variant in ERBB3 (c.1946 T > G: p.Iso649Arg), coding for receptor tyrosine-protein kinase erbB-3 (ErbB3), was identified, with appropriate segregation. There was no loss-of-heterozygosity in tumour samples. Both wtErbB3 and mutErbB3 were stably expressed. MutErbB3-transfected cells demonstrated an increased ratio of the 80 kDa form (which enhances proliferation) compared with the full-length (180 kDa) form. MutErbB3 and wtErbB3 had similar punctate cytoplasmic localization pre- and post-epidermal growth factor stimulation; however, epidermal growth factor receptor (EGFR) levels decreased faster post-stimulation in mutErbB3-transfected cells, suggesting more rapid processing of the mutErbB3/EGFR heterodimer. Cellular proliferation was increased in mutErbB3-transfected cells compared with wtErbB3 transfection. MutErbB3-transfected cells also showed decreased pAkt/tAkt ratios and increased pERK/tERK 30 min post-stimulation compared with wtErbB3 transfection, demonstrating altered signalling pathway activation. Cumulatively, these results support this mutation as tumorogenic. This is the first reported family with a germline ERBB3 mutation causing heritable NSCLC, furthering understanding of the ErbB family pathway in oncogenesis.
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Affiliation(s)
- Aideen M McInerney-Leo
- The Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102
| | - Hui Yi Chew
- The Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102
| | - Po-Ling Inglis
- Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD, 4029
| | - Paul J Leo
- Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102
| | - Shannon R Joseph
- The Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102
| | - Caroline L Cooper
- Department of Anatomical Pathology, Pathology Queensland, Princess Alexandra Hospital, Brisbane.,UQTRC, Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD, 4006
| | - Satomi Okano
- The Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102
| | - Tim Hassall
- Queensland Children's Hospital, South Brisbane, QLD, 4101
| | - Lisa Anderson
- Medical Oncology, Royal Brisbane and Women's Hospital, Herston, QLD, 4029
| | - Rayleen V Bowman
- UQTRC, Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD, 4006.,Department of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, QLD, 4032
| | - Michael Gattas
- Genetic Health Queensland, Royal Brisbane and Women's Hospital, Herston, QLD, 4029
| | - Jessica E Harris
- Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102
| | - Mhairi S Marshall
- Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102
| | - Janet G Shaw
- UQTRC, Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD, 4006.,Department of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, QLD, 4032
| | - Lawrie Wheeler
- Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102
| | - Ian A Yang
- UQTRC, Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD, 4006.,Department of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, QLD, 4032
| | - Matthew A Brown
- Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102.,Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.,King's College London NIHR Biomedical Research Centre, King's College London, United Kingdom
| | - Kwun M Fong
- UQTRC, Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD, 4006.,Department of Thoracic Medicine, The Prince Charles Hospital, Rode Road, Chermside, QLD, 4032
| | - Fiona Simpson
- The Dermatology Research Centre, The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, 4102
| | - Emma L Duncan
- Australian Translational Genomics Centre, Institute of Health and Biomedical Innovation, School of Biomedical Sciences, Queensland University of Technology (QUT), Translational Research Institute, 37 Kent St, Woolloongabba, QLD, 4102.,UQTRC, Faculty of Medicine, The University of Queensland, 288 Herston Road, Herston, QLD, 4006.,Department of Twin Research and Genetic Epidemiology, Faculty of Life Sciences and Medicine, King's College London, United Kingdom
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28
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Asano T, Ohishi T, Takei J, Nakamura T, Nanamiya R, Hosono H, Tanaka T, Sano M, Harada H, Kawada M, Kaneko MK, Kato Y. Anti‑HER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma. Oncol Rep 2021; 46:173. [PMID: 34184091 PMCID: PMC8261196 DOI: 10.3892/or.2021.8124] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 05/21/2021] [Indexed: 01/10/2023] Open
Abstract
HER3 belongs to the epidermal growth factor receptor (EGFR) family and is known to form an active heterodimer with other three family members EGFR, HER2, and HER4. HER3 is overexpressed in lung, breast, colon, prostate, and gastric cancers. In the present study, we developed and validated an anti-HER3 monoclonal antibody (mAb), H3Mab-17 (IgG2a, kappa), by immunizing mice with HER3-overexpressed CHO-K1 cells (CHO/HER3). H3Mab-17 was found to react specifically with endogenous HER3 in colorectal carcinoma cell lines, using flow cytometry. The KD for H3Mab-17 in CHO/HER3 and Caco-2 (a colon cancer cell line) were determined to be 3.0×10−9 M and 1.5×10−9 M via flow cytometry, respectively, suggesting high binding affinity of H3Mab-17 to HER3. Then, we assessed the H3Mab-17 antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) against Caco-2, and evaluated its antitumor capacity in a Caco-2 ×enograft model. In vitro experiments revealed H3Mab-17 had strongly induced both ADCC and CDC against Caco-2 cells. In vivo experiments on Caco-2 ×enografts revealed that H3Mab-17 treatment significantly reduced tumor growth compared with the control mouse IgG. These data indicated that H3Mab-17 could be a promising treatment option for HER3-expressing colon cancers.
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Affiliation(s)
- Teizo Asano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Tomokazu Ohishi
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu‑shi, Shizuoka 410‑0301, Japan
| | - Junko Takei
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Takuro Nakamura
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Ren Nanamiya
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Hideki Hosono
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Tomohiro Tanaka
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Masato Sano
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Hiroyuki Harada
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Bunkyo‑ku, Tokyo 113‑8510, Japan
| | - Manabu Kawada
- Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu‑shi, Shizuoka 410‑0301, Japan
| | - Mika K Kaneko
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
| | - Yukinari Kato
- Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan
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29
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Nishiyama K, Maekawa M, Nakagita T, Nakayama J, Kiyoi T, Chosei M, Murakami A, Kamei Y, Takeda H, Takada Y, Higashiyama S. CNKSR1 serves as a scaffold to activate an EGFR phosphatase via exclusive interaction with RhoB-GTP. Life Sci Alliance 2021; 4:4/9/e202101095. [PMID: 34187934 PMCID: PMC8321701 DOI: 10.26508/lsa.202101095] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 12/15/2022] Open
Abstract
CNKSR1 functions as a scaffold protein for activation of an EGFR phosphatase, PTPRH, at the plasma membrane through the exclusive interaction with RhoB-GTP which is constitutively degraded by the CUL3/KCTD10 E3 complex. Epidermal growth factor receptor (EGFR) and human EGFR 2 (HER2) phosphorylation drives HER2-positive breast cancer cell proliferation. Enforced activation of phosphatases for those receptors could be a therapeutic option for HER2-positive breast cancers. Here, we report that degradation of an endosomal small GTPase, RhoB, by the ubiquitin ligase complex cullin-3 (CUL3)/KCTD10 is essential for both EGFR and HER2 phosphorylation in HER2-positive breast cancer cells. Using human protein arrays produced in a wheat cell-free protein synthesis system, RhoB-GTP, and protein tyrosine phosphatase receptor type H (PTPRH) were identified as interacting proteins of connector enhancer of kinase suppressor of Ras1 (CNKSR1). Mechanistically, constitutive degradation of RhoB, which is mediated by the CUL3/KCTD10 E3 complex, enabled CNKSR1 to interact with PTPRH at the plasma membrane resulting in inactivation of EGFR phosphatase activity. Depletion of CUL3 or KCTD10 led to the accumulation of RhoB-GTP at the plasma membrane followed by its interaction with CNKSR1, which released activated PTPRH from CNKSR1. This study suggests a mechanism of PTPRH activation through the exclusive binding of RhoB-GTP to CNKSR1.
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Affiliation(s)
- Kanako Nishiyama
- Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan.,Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan
| | - Masashi Maekawa
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan .,Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Japan
| | - Tomoya Nakagita
- Division of Proteo-Drug-Discovery Sciences, Proteo-Science Center, Ehime University, Matsuyama, Japan
| | - Jun Nakayama
- Division of Cellular Signaling, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Takeshi Kiyoi
- Division of Analytical Bio-medicine, Advanced Research Support Center, Ehime University, Toon, Japan
| | - Mami Chosei
- Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Japan
| | - Akari Murakami
- Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Yoshiaki Kamei
- Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Hiroyuki Takeda
- Division of Proteo-Drug-Discovery Sciences, Proteo-Science Center, Ehime University, Matsuyama, Japan
| | - Yasutsugu Takada
- Department of Hepato-Biliary-Pancreatic Surgery and Breast Surgery, Ehime University Graduate School of Medicine, Toon, Japan
| | - Shigeki Higashiyama
- Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Toon, Japan .,Division of Cell Growth and Tumor Regulation, Proteo-Science Center, Ehime University, Toon, Japan.,Department of Molecular and Cellular Biology, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan
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30
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Senger K, Yuan W, Sagolla M, Doerr J, Bolon B, Ziai J, Sun K, Warming S, Roose‐Girma M, Zhang N, Tam L, Newman RJ, Chaudhuri S, Antony A, Goldstein LD, Durinck S, Jaiswal BS, Lafkas D, Modrusan Z, Seshagiri S. Embryonic lethality and defective mammary gland development of activator-function impaired conditional knock-in Erbb3 V943R mice. ADVANCED GENETICS (HOBOKEN, N.J.) 2021; 2:e10036. [PMID: 36618440 PMCID: PMC9744554 DOI: 10.1002/ggn2.10036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 11/16/2020] [Accepted: 11/16/2020] [Indexed: 01/11/2023]
Abstract
ERBB3 is a pseudokinase domain-containing member of the ERBB family of receptor tyrosine kinases (RTKs). Following ligand binding, ERBB receptors homo- or hetero-dimerize, leading to a head-to-tail arrangement of the intracellular kinase domains, where the "receiver" kinase domain of one ERBB is activated by the "activator" domain of the other ERBB in the dimer. In ERBB3, a conserved valine at codon 943 (V943) in the kinase C-terminal domain has been shown to be important for its function as an "activator" kinase in vitro. Here we report a knock-in mouse model where we have modified the endogenous Erbb3 allele to allow for tissue-specific conditional expression of Erbb3 V943R (Erbb3 CKI-V943R ). Additionally, we generated an Erbb3 D850N (Erbb3 CKI-D850N ) conditional knock-in mouse model where the conserved aspartate in the DFG motif of the pseudokinase domain was mutated to abolish any potential residual kinase activity. While Erbb3 D850N/D850N animals developed normally, homozygous Erbb3 V943R/V943R expression during development resulted in embryonic lethality. Further, tissue specific expression of Erbb3 V943R/V943R in the mammary gland epithelium following its activation using MMTV-Cre resulted in delayed elongation of the ductal network during puberty. Single-cell RNA-seq analysis of Erbb3 V943R/V943R mammary glands showed a reduction in a specific subset of fibrinogen-producing luminal epithelial cells.
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Affiliation(s)
- Kate Senger
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Wenlin Yuan
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Meredith Sagolla
- Department of PathologyGenentechSouth San FranciscoCaliforniaUSA
| | - Jonas Doerr
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | | | - James Ziai
- Department of PathologyGenentechSouth San FranciscoCaliforniaUSA
| | - Kai‐Hui Sun
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Soren Warming
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Merone Roose‐Girma
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Na Zhang
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Lucinda Tam
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Robert J. Newman
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Subhra Chaudhuri
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | | | - Leonard D. Goldstein
- Department of Bioinformatics and Computational BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Steffen Durinck
- Department of Bioinformatics and Computational BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Bijay S. Jaiswal
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Daniel Lafkas
- Department of Immunology DiscoveryGenentechSouth San FranciscoCaliforniaUSA
| | - Zora Modrusan
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
| | - Somasekar Seshagiri
- Department of Molecular BiologyGenentechSouth San FranciscoCaliforniaUSA
- SciGenom Research FoundationBangaloreKarnatakaIndia
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Zhang BY, Zhang L, Chen YM, Qiao X, Zhao SL, Li P, Liu JF, Wen X, Yang J. Corosolic acid inhibits colorectal cancer cells growth as a novel HER2/HER3 heterodimerization inhibitor. Br J Pharmacol 2021; 178:1475-1491. [PMID: 33443775 DOI: 10.1111/bph.15372] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 12/24/2020] [Accepted: 12/30/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND AND PURPOSE Colorectal cancer is the third most common cancer worldwide. HER2 and HER3 are two members of human epidermal receptor family of tyrosine kinase receptors (RTKs) and associated with poor survival in colorectal cancer. They have been observed as important therapeutic targets in various types of cancer. Corosolic acid, a natural pentacyclic triterpene, has been demonstrated to have a significant anti-cancer activity. However, the target of corosolic acid has not yet been explored. This study aimed to reveal the direct targets of corosolic acid underlying its anti-cancer activities. EXPERIMENTAL APPROACH The targets of corosolic acid were revealed by the phospho-RTK array, bio-layer interferometry, co-immunoprecipitation, and proximity ligation assay. The inhibitory action of corosolic acid on HER2/HER3 heterodimerization and related downstream signalling were investigated in HCT116 and SW480 cells. In addition, the chemo-preventive effects of corosolic acid were validated in both HCT116 xenograft model and AOM/DSS model. KEY RESULTS Our results demonstrated that corosolic acid could prevent NRG1-induced HER2/HER3 heterodimerization and suppress the phosphorylation of both HER2 and HER3. Furthermore, HER2 and HER3 could regulate the downstream signalling pathways of RalA/RalBP1/CDK1 and PI3K/Akt/PKA, respectively, resulting in the changes in phosphorylation of Drp1 and mitochondrial dynamics. corosolic acid exhibited anti-cancer activity in both HCT116 xenograft model and AOM/DSS model. CONCLUSIONS AND IMPLICATIONS Collectively, our results demonstrated corosolic acid directly targeted HER2 and HER3 heterodimerization and inhibited mitochondrial fission via regulating RalA/RalBP1/CDK1 and PI3K/Akt/PKA pathways, revealing a novel mechanism underlying the beneficial effects of corosolic acid on colorectal cancer.
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Affiliation(s)
- Bi-Ying Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Lei Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Yi-Meng Chen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xin Qiao
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Shu-Ling Zhao
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jin-Feng Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Xiaodong Wen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
| | - Jie Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, China
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Zhao J, Mohan N, Nussinov R, Ma B, Wu WJ. Trastuzumab Blocks the Receiver Function of HER2 Leading to the Population Shifts of HER2-Containing Homodimers and Heterodimers. Antibodies (Basel) 2021; 10:7. [PMID: 33557368 PMCID: PMC7931022 DOI: 10.3390/antib10010007] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 01/15/2021] [Accepted: 01/27/2021] [Indexed: 11/16/2022] Open
Abstract
HER2, a member of the Erythroblastosis Protein B/Human Epidermal Growth Factor Receptor (ErbB/HER) family of receptor tyrosine kinase, is overexpressed in 20~30% of human breast cancers. Trastuzumab, a HER2-targeted therapeutic monoclonal antibody, was developed to interfere with the homodimerization of HER2 in HER2-overexpressing breast cancer cells, which attenuates HER2-mediated signaling. Trastuzumab binds to the domain IV of the HER2 extracellular domain and does not directly block the dimerization interface of HER2-HER2 molecules. The three-dimensional structures of the tyrosine kinase domains of ErbB/HER family receptors show asymmetrical packing of the two monomers with distinct conformations. One monomer functions as an activator, whereas the other acts as a receiver. Once activated, the receiver monomer phosphorylates the activator or other proteins. Interestingly, in our previous work, we found that the binding of trastuzumab induced phosphorylation of HER2 with the phosphorylation pattern of HER2 that is different from that mediated by epidermal growth factor (EGF) in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Binding of trastuzumab to HER2 promoted an allosteric effect of HER2, in both tyrosine kinase domain and ectodomain of HER2 although details of allosteric regulation were missing. In this study, we utilized molecular dynamics (MD) simulations to model the allosteric consequences of trastuzumab binding to HER2 homodimers and heterodimers, along with the apo forms as controls. We focused on the conformational changes of HER2 in its monomeric and dimeric forms. The data indicated the apparent dual role of trastuzumab as an antagonist and an agonist. The molecular details of the simulation provide an atomic level description and molecular insight into the action of HER2-targeted antibody therapeutics.
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Affiliation(s)
- Jun Zhao
- Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA;
- Interagency Oncology Task Force (IOTF) Fellowship: Oncology Product Research/Review Fellow, National Cancer Institute, Bethesda, MD 20892, USA
| | - Nishant Mohan
- Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA;
| | - Ruth Nussinov
- Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA; (R.N.)
| | - Buyong Ma
- Basic Science Program, Leidos Biomedical Research, Inc., Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, USA; (R.N.)
| | - Wen Jin Wu
- Division of Biotechnology Review and Research 1, Office of Biotechnology Products, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Avenue, Silver Spring, MD 20993, USA;
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Gutsch D, Jenke R, Büch T, Aigner A. Inhibition of HER Receptors Reveals Distinct Mechanisms of Compensatory Upregulation of Other HER Family Members: Basis for Acquired Resistance and for Combination Therapy. Cells 2021; 10:272. [PMID: 33572976 PMCID: PMC7911202 DOI: 10.3390/cells10020272] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/22/2021] [Accepted: 01/25/2021] [Indexed: 12/02/2022] Open
Abstract
Overexpression of members of the HER/erbB transmembrane tyrosine kinase family like HER2/erbB2/neu is associated with various cancers. Some heterodimers, especially HER2/HER3 heterodimers, are particularly potent inducers of oncogenic signaling. Still, from a clinical viewpoint their inhibition has yielded only moderate success so far, despite promising data from cell cultures. This suggests acquired resistance upon inhibitor therapy as one putative issue, requiring further studies in cell culture also aiming at rational combination therapies. In this paper, we demonstrate in ovarian carcinoma cells that the RNAi-mediated single knockdown of HER2 or HER3 leads to the rapid counter-upregulation of the respective other HER family member, thus providing a rational basis for combinatorial inhibition. Concomitantly, combined knockdown of HER2/HER3 exerts stronger anti-tumor effects as compared to single inhibition. In a tumor cell line xenograft mouse model, therapeutic intervention with nanoscale complexes based on polyethylenimine (PEI) for siRNA delivery, again reveals HER3 upregulation upon HER2 single knockdown and a therapeutic benefit from combination therapy. On the mechanistic side, we demonstrate that HER2 knockdown or inhibition reduces miR-143 levels with subsequent de-repression of HER3 expression, and validates HER3 as a direct target of miR-143. HER3 knockdown or inhibition, in turn, increases HER2 expression through the upregulation of the transcriptional regulator SATB1. These counter-upregulation processes of HER family members are thus based on distinct molecular mechanisms and may provide the basis for the rational combination of inhibitors.
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Affiliation(s)
- Daniela Gutsch
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D-04107 Leipzig, Germany; (D.G.); (R.J.); (T.B.)
| | - Robert Jenke
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D-04107 Leipzig, Germany; (D.G.); (R.J.); (T.B.)
- University Cancer Center Leipzig (UCCL), University Hospital Leipzig, D-04103 Leipzig, Germany
| | - Thomas Büch
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D-04107 Leipzig, Germany; (D.G.); (R.J.); (T.B.)
| | - Achim Aigner
- Rudolf-Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Faculty of Medicine, University of Leipzig, D-04107 Leipzig, Germany; (D.G.); (R.J.); (T.B.)
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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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Al-Yozbaki M, Acha-Sagredo A, George A, Liloglou T, Wilson CM. Balancing neurotrophin pathway and sortilin function: Its role in human disease. Biochim Biophys Acta Rev Cancer 2020; 1874:188429. [DOI: 10.1016/j.bbcan.2020.188429] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 08/12/2020] [Accepted: 09/02/2020] [Indexed: 01/03/2023]
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Zangouei AS, Barjasteh AH, Rahimi HR, Mojarrad M, Moghbeli M. Role of tyrosine kinases in bladder cancer progression: an overview. Cell Commun Signal 2020; 18:127. [PMID: 32795296 PMCID: PMC7427778 DOI: 10.1186/s12964-020-00625-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 07/02/2020] [Indexed: 12/20/2022] Open
Abstract
Background Bladder cancer (BCa) is a frequent urothelial malignancy with a high ratio of morbidity and mortality. Various genetic and environmental factors are involved in BCa progression. Since, majority of BCa cases are diagnosed after macroscopic clinical symptoms, it is required to find efficient markers for the early detection. Receptor tyrosine-kinases (RTKs) and non-receptor tyrosine-kinases (nRTKs) have pivotal roles in various cellular processes such as growth, migration, differentiation, and metabolism through different signaling pathways. Tyrosine-kinase deregulations are observed during tumor progressions via mutations, amplification, and chromosomal abnormalities which introduces these factors as important candidates of anti-cancer therapies. Main body For the first time in present review we have summarized all of the reported tyrosine-kinases which have been significantly associated with the clinicopathological features of BCa patients. Conclusions This review highlights the importance of tyrosine-kinases as critical markers in early detection and therapeutic purposes among BCa patients and clarifies the molecular biology of tyrosine-kinases during BCa progression and metastasis.
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