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      In vitro and in vivo Anti-Tumor Effects of Pan-HER Inhibitor Varlitinib on Cholangiocarcinoma Cell Lines

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          Abstract

          Background

          Cholangiocarcinoma (CCA) is a slowly progressing but highly aggressive malignancy. Targeting the HER protein family represents a potential therapeutic strategy for CCA treatment. The pan-HER inhibitor varlitinib is being developed for the treatment of breast cancer, gastric cancer, and biliary tract cancer, which includes CCA. This study aims to evaluate the anti-tumor effect of varlitinib on CCA using both in vitro and in vivo models.

          Materials and Methods

          HER family expression profiles and the cytotoxic activity of varlitinib were determined in CCA cell lines (KKU-214, KKU-213, KKU-156 and KKU-100) and cholangiocyte (MMNK-1). Anti-proliferation and apoptosis induction were examined in KKU-214 and KKU-100 cell lines. A combination of varlitinib with PI3K inhibitor, BKM-120, was explored for efficacy in the KKU-100 cell line. In addition, the anti-tumor activity of varlitinib on CCA and the key metabolites were evaluated in tumor tissues from CCA xenograft model.

          Results

          Elevated expressions of EGFR and HER2 were observed in KKU-214 and KKU-100 cells and varlitinib can suppress CCA cell growth in the micromolar range. Varlitinib inhibits cell proliferation and enhances cell death via the suppression of Akt and Erk1/2 activity in the KKU-214 cell line. While KKU-100 cells showed a poor response to varlitinib, a combination of varlitinib with BKM-120 improved anti-tumor activity. Varlitinib can significantly suppress tumor growth in the CCA xenograft model after oral administration for 15 days without noticeable toxicity, and aspartate can be the key metabolite to correlate with varlitinib response.

          Conclusion

          Our study indicates that varlitinib is a promising therapeutic agent for CCA treatment via the inhibition of EGFR/HER2. The anti-tumor effect of varlitinib on CCA also showed synergism in combination with PI3K inhibition. Aspartate metabolite level was correlated with varlitinib response. Combination of varlitinib with targeted drug or cytotoxic drug was recommended.

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          Most cited references 26

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          The EGFR family and its ligands in human cancer. signalling mechanisms and therapeutic opportunities.

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          Growth factors and their transmembrane receptor tyrosine kinases play important roles in cell proliferation, survival, migration and differentiation. One group of growth factors, comprising epidermal growth factor (EGF)-like proteins and neuregulins, stimulates cells to divide by activating members of the EGF receptor (EGFR) family, which consists of the EGFR itself and the receptors known as HER2-4. This highly conserved signalling module plays a fundamental role in the morphogenesis of a diverse spectrum of organisms, ranging from humans to nematodes, and has also been implicated in the development and growth of many types of human tumour cells. In humans, more than 30 ligands and the EGFR family of four receptors lie at the head of a complex, multi-layered signal-transduction network. Different activated receptor-ligand complexes vary in both the strength and type of cellular responses that they induce. Analysis of the multiple processes that modulate EGFR signal transduction, such as receptor heterodimerisation and endocytosis, has revealed new therapeutic opportunities and elucidated mechanisms contributing to the efficacy of existing anticancer treatments.
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            Oncogenic ERBB3 mutations in human cancers.

            The human epidermal growth factor receptor (HER) family of tyrosine kinases is deregulated in multiple cancers either through amplification, overexpression, or mutation. ERBB3/HER3, the only member with an impaired kinase domain, although amplified or overexpressed in some cancers, has not been reported to carry oncogenic mutations. Here, we report the identification of ERBB3 somatic mutations in ~11% of colon and gastric cancers. We found that the ERBB3 mutants transformed colonic and breast epithelial cells in a ligand-independent manner. However, the mutant ERBB3 oncogenic activity was dependent on kinase-active ERBB2. Furthermore, we found that anti-ERBB antibodies and small molecule inhibitors effectively blocked mutant ERBB3-mediated oncogenic signaling and disease progression in vivo. Copyright © 2013 Elsevier Inc. All rights reserved.
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              The epidermal growth factor family of receptor tyrosine kinases (ErbBs) plays essential roles in regulating cell proliferation, survival, differentiation and migration. The ErbB receptors carry out both redundant and restricted functions in mammalian development and in the maintenance of tissues in the adult mammal. Loss of regulation of the ErbB receptors underlies many human diseases, most notably cancer. Our understanding of the function and complex regulation of these receptors has fueled the development of targeted therapeutic agents for human malignancies in the last 15 years. Here we review the biology of ErbB receptors, including their structure, signaling, regulation, and roles in development and disease, then briefly touch on their increasing roles as targets for cancer therapy.
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                Author and article information

                Journal
                Drug Des Devel Ther
                Drug Des Devel Ther
                DDDT
                dddt
                Drug Design, Development and Therapy
                Dove
                1177-8881
                11 June 2020
                2020
                : 14
                : 2319-2334
                Affiliations
                [1 ]Cholangiocarcinoma Screening and Care Program (CASCAP), Faculty of Medicine, Khon Kaen University , Khon Kaen 40002, Thailand
                [2 ]Cholangiocarcinoma Research Institute, Khon Kaen University , Khon Kaen 40002, Thailand
                [3 ]Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen 40002, Thailand
                [4 ]Department of Pathology, Faculty of Medicine, Khon Kaen University , Khon Kaen 40002, Thailand
                [5 ]Department of Surgery, Faculty of Medicine, Khon Kaen University , Khon Kaen 40002, Thailand
                Author notes
                Correspondence: Watcharin Loilome Department of Biochemistry, Faculty of Medicine, Khon Kaen University , Khon Kaen40002, Thailand Tel/Fax +66 43 348 386 Email watclo@kku.ac.th
                Article
                250061
                10.2147/DDDT.S250061
                7296552
                © 2020 Dokduang et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                Page count
                Figures: 8, References: 38, Pages: 16
                Categories
                Original Research

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