دورية أكاديمية
أعرض في EDS

Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor.

التفاصيل البيبلوغرافية
العنوان: Upregulation of the ErbB family by EZH2 in hepatocellular carcinoma confers resistance to FGFR inhibitor.
المؤلفون: Prawira A; Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Le TBU; Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Ho RZW; Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore., Huynh H; Laboratory of Molecular Endocrinology, Division of Cellular and Molecular Research, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore. cmrhth@nccs.com.sg.
المصدر: Journal of cancer research and clinical oncology [J Cancer Res Clin Oncol] 2021 Oct; Vol. 147 (10), pp. 2955-2968. Date of Electronic Publication: 2021 Jun 22.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Springer-Verlag Country of Publication: Germany NLM ID: 7902060 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1432-1335 (Electronic) Linking ISSN: 01715216 NLM ISO Abbreviation: J Cancer Res Clin Oncol Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Berlin ; New York : Springer-Verlag.
مواضيع طبية MeSH: Antineoplastic Combined Chemotherapy Protocols/*pharmacology , Carcinoma, Hepatocellular/*drug therapy , Drug Resistance, Neoplasm/*drug effects , Enhancer of Zeste Homolog 2 Protein/*metabolism , Gene Expression Regulation, Neoplastic/*drug effects , Receptor, ErbB-2/*metabolism , Receptor, Fibroblast Growth Factor, Type 1/*antagonists & inhibitors, Animals ; Antibodies, Monoclonal, Humanized/administration & dosage ; Apoptosis ; Biomarkers, Tumor/genetics ; Biomarkers, Tumor/metabolism ; Carcinoma, Hepatocellular/metabolism ; Carcinoma, Hepatocellular/pathology ; Cell Proliferation ; Enhancer of Zeste Homolog 2 Protein/genetics ; Humans ; Liver Neoplasms/drug therapy ; Liver Neoplasms/metabolism ; Liver Neoplasms/pathology ; Male ; Mice ; Mice, SCID ; Phenylurea Compounds/administration & dosage ; Protein Kinase Inhibitors/pharmacology ; Pyrimidines/administration & dosage ; Receptor, ErbB-2/genetics ; Tumor Cells, Cultured ; Xenograft Model Antitumor Assays
مستخلص: Purpose: Hepatocellular carcinoma (HCC), the most common manifestation of liver cancer, is one of the leading causes of cancer-related mortality worldwide with limited treatment options. Infigratinib, a pan-FGFR inhibitor, has shown a potent antitumour effect in HCC. However, drug resistance is often observed in long-term treatment. In this study, we examined the potential feedback mechanism(s) leading to infigratinib and explored a combination therapy to overcome resistance in HCC.
Methods: Patient-derived xenograft (PDX) tumours were subcutaneously implanted into SCID mice and were subsequently treated with infigratinib. Tumour growth was monitored over time, and tumour samples were subjected to immunohistochemistry and Western blotting. For drug combination studies, mice were treated with infigratinib and/or varlitinib. Gene overexpression and knockdown studies were conducted to investigate the relationship between EZH2 and ErbB activity in infigratinib resistance.
Results: Infigratinib-resistant tumours exhibited higher levels of p-ErbB2 and p-ErbB3, concomitant with an increase in EZH2 expression. Gene overexpression and knockdown studies revealed that EZH2 directly regulates the levels of p-ErbB2 and p-ErbB3 in acquired resistance to infigratinib. The addition of varlitinib effectively overcame infigratinib resistance and prolonged the antitumour response, with minimal toxicity.
Conclusion: The upregulation of the ErbB family by EZH2 appears to contribute to infigratinib resistance. The combination of infigratinib and varlitinib showed a potent antitumour effect and did not result in additional toxicity, warranting further clinical investigation.
(© 2021. The Author(s).)
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معلومات مُعتمدة: NMRC/MOHIAFCat2/006/2016 Singapore National Medical Research Council; NMRC/MOHIAFCat1/0026/2015 Singapore National Medical Research Council; NMRC/MOHIAFCat1/0009/2014 Singapore National Medical Research Council; CGAug16M005 RIE2020 NCIS Centre Grant; NRF-CRP17-2017-05 National Research Foundation Singapore
فهرسة مساهمة: Keywords: Hepatocellular carcinoma; Infigratinib; Liver cancer; Varlitinib
المشرفين على المادة: 0 (Antibodies, Monoclonal, Humanized)
0 (Biomarkers, Tumor)
0 (Phenylurea Compounds)
0 (Protein Kinase Inhibitors)
0 (Pyrimidines)
0125DUV5XC (varlilumab)
A4055ME1VK (infigratinib)
EC 2.1.1.43 (EZH2 protein, human)
EC 2.1.1.43 (Enhancer of Zeste Homolog 2 Protein)
EC 2.7.10.1 (ERBB2 protein, human)
EC 2.7.10.1 (FGFR1 protein, human)
EC 2.7.10.1 (Receptor, ErbB-2)
EC 2.7.10.1 (Receptor, Fibroblast Growth Factor, Type 1)
تواريخ الأحداث: Date Created: 20210622 Date Completed: 20210913 Latest Revision: 20220218
رمز التحديث: 20221213
مُعرف محوري في PubMed: PMC8397639
DOI: 10.1007/s00432-021-03703-6
PMID: 34156519
قاعدة البيانات: MEDLINE
الوصف
تدمد:1432-1335
DOI:10.1007/s00432-021-03703-6