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      HER3-targeted therapy: the mechanism of drug resistance and the development of anticancer drugs

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          Abstract

          Human epidermal growth factor receptor 3 (HER3), which is part of the HER family, is aberrantly expressed in various human cancers. Since HER3 only has weak tyrosine kinase activity, when HER3 ligand neuregulin 1 (NRG1) or neuregulin 2 (NRG2) appears, activated HER3 contributes to cancer development and drug resistance by forming heterodimers with other receptors, mainly including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Inhibition of HER3 and its downstream signaling, including PI3K/AKT, MEK/MAPK, JAK/STAT, and Src kinase, is believed to be necessary to conquer drug resistance and improve treatment efficiency. Until now, despite multiple anti-HER3 antibodies undergoing preclinical and clinical studies, none of the HER3-targeted therapies are licensed for utilization in clinical cancer treatment because of their safety and efficacy. Therefore, the development of HER3-targeted drugs possessing safety, tolerability, and sensitivity is crucial for clinical cancer treatment. This review summarizes the progress of the mechanism of HER3 in drug resistance, the HER3-targeted therapies that are conducted in preclinical and clinical trials, and some emerging molecules that could be used as future designed drugs for HER3, aiming to provide insights for future research and development of anticancer drugs targeting HER3.

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          Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries

          Hyuna Sung, Jacques Ferlay, Rebecca Siegel … (2021)
          This article provides an update on the global cancer burden using the GLOBOCAN 2020 estimates of cancer incidence and mortality produced by the International Agency for Research on Cancer. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding nonmelanoma skin cancer) and almost 10.0 million cancer deaths (9.9 million excluding nonmelanoma skin cancer) occurred in 2020. Female breast cancer has surpassed lung cancer as the most commonly diagnosed cancer, with an estimated 2.3 million new cases (11.7%), followed by lung (11.4%), colorectal (10.0 %), prostate (7.3%), and stomach (5.6%) cancers. Lung cancer remained the leading cause of cancer death, with an estimated 1.8 million deaths (18%), followed by colorectal (9.4%), liver (8.3%), stomach (7.7%), and female breast (6.9%) cancers. Overall incidence was from 2-fold to 3-fold higher in transitioned versus transitioning countries for both sexes, whereas mortality varied <2-fold for men and little for women. Death rates for female breast and cervical cancers, however, were considerably higher in transitioning versus transitioned countries (15.0 vs 12.8 per 100,000 and 12.4 vs 5.2 per 100,000, respectively). The global cancer burden is expected to be 28.4 million cases in 2040, a 47% rise from 2020, with a larger increase in transitioning (64% to 95%) versus transitioned (32% to 56%) countries due to demographic changes, although this may be further exacerbated by increasing risk factors associated with globalization and a growing economy. Efforts to build a sustainable infrastructure for the dissemination of cancer prevention measures and provision of cancer care in transitioning countries is critical for global cancer control.
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            Bispecific antibodies: a mechanistic review of the pipeline

            Aran F Labrijn, Maarten Janmaat, Janice M. Reichert … (2019)
            The term bispecific antibody (bsAb) is used to describe a large family of molecules designed to recognize two different epitopes or antigens. BsAbs come in many formats, ranging from relatively small proteins, merely consisting of two linked antigen-binding fragments, to large immunoglobulin G (IgG)-like molecules with additional domains attached. An attractive bsAb feature is their potential for novel functionalities - that is, activities that do not exist in mixtures of the parental or reference antibodies. In these so-called obligate bsAbs, the physical linkage of the two binding specificities creates a dependency that can be temporal, with binding events occurring sequentially, or spatial, with binding events occurring simultaneously, such as in linking an effector to a target cell. To date, more than 20 different commercialized technology platforms are available for bsAb creation and development, 2 bsAbs are marketed and over 85 are in clinical development. Here, we review the current bsAb landscape from a mechanistic perspective, including a comprehensive overview of the pipeline.
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              MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling.

              Jeffrey A. Engelman, Kreshnik Zejnullahu, Tetsuya Mitsudomi … (2007)
              The epidermal growth factor receptor (EGFR) kinase inhibitors gefitinib and erlotinib are effective treatments for lung cancers with EGFR activating mutations, but these tumors invariably develop drug resistance. Here, we describe a gefitinib-sensitive lung cancer cell line that developed resistance to gefitinib as a result of focal amplification of the MET proto-oncogene. inhibition of MET signaling in these cells restored their sensitivity to gefitinib. MET amplification was detected in 4 of 18 (22%) lung cancer specimens that had developed resistance to gefitinib or erlotinib. We find that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)-dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors. Thus, we propose that MET amplification may promote drug resistance in other ERBB-driven cancers as well.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Cancer Drug Resist
                Journal ID (iso-abbrev): Cancer Drug Resist
                Journal ID (publisher-id): CDR
                Title: Cancer Drug Resistance
                Publisher: OAE Publishing Inc.
                ISSN (Electronic): 2578-532X
                Publication date Collection: 2024
                Publication date (Electronic): 29 April 2024
                Volume: 7
                Electronic Location Identifier: 14
                Affiliations
                1School of Life Sciences, Chongqing University, Chongqing 401331, China.
                2Department of Cancer Center, Chongqing University Three Gorges Hospital, School of Medicine, Chongqing University, Chongqing 404000, China.
                3Department of Gastroenterology, Chongqing University Jiangjin Hospital, Chongqing 402260, China.
                Author notes
                Correspondence to: Prof. Zhenghong Lin, School of Life Sciences, Chongqing University, South Rd. No. 55, University Town, Chongqing 401331, China. E-mail: zhenghonglin@ 123456cqu.edu.cdu.cn ; Dr. Lin Zhang, Department of Gastroenterology, Chongqing University Jiangjin Hospital, Dingshan Street, Jiangzhou Rd. No.725, Jiangjin District, Chongqing 402260, China. E-mail: brucezhanglin@ 123456cqu.edu.cn ; Dr. Wei Wang, Department of Cancer Center, Chongqing University Three Gorges Hospital, School of Medicine, Xincheng Rd. No. 165, Wanzhou District, Chongqing 404000, China. E-mail: wangwei929@ 123456cqu.edu.cn

                Academic Editor: Elisa Giovannetti | Copy Editor: Dong-Li Li | Production Editor: Dong-Li Li

                Article
                DOI: 10.20517/cdr.2024.11
                PMC ID: 11149107
                PubMed ID: 38835349
                SO-VID: bfe977b7-0e5a-4202-a5a0-12f81eb8fa51
                Copyright © © The Author(s) 2024.
                License:

                © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 21 January 2024
                Date revision received : 04 April 2024
                Date accepted : 23 April 2024
                Funding
                Funded by: supported by the National Natural Science Foundation of China (Grant No. 82172888)
                Funded by: Project the Fundamental Research Funds for the Central Universities (Grant No. 2023CDJYGRH-YB07 and Grant No. 2023CDJXY-009)
                Categories
                Subject: Review

                Keywords: her3,molecular mechanism,drug resistance,targeted therapy,monoclonal antibody,molecular target
                Data availability:
                Keywords: her3, molecular mechanism, drug resistance, targeted therapy, monoclonal antibody, molecular target

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