دورية أكاديمية
أعرض في EDS

Calcium Channel Blockers Impair the Antitumor Activity of Anti-CD20 Monoclonal Antibodies by Blocking EGR-1 Induction.

التفاصيل البيبلوغرافية
العنوان: Calcium Channel Blockers Impair the Antitumor Activity of Anti-CD20 Monoclonal Antibodies by Blocking EGR-1 Induction.
المؤلفون: Spasevska I; Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Matera EL; Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Chettab K; Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Ville J; Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Potier-Cartereau M; Inserm/University of Tours U1069, Nutrition-Croissance et Cancer (N2C), Tours, France., Jordheim LP; Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France., Thieblemont C; Hemato-Oncology, Hospital Saint-Louis, APHP, Paris, France., Sahin D; Pharma Development Oncology, F. Hoffmann-La Roche, Basel, Switzerland., Klein C; Roche Pharmaceutical Research and Early Development, Roche Innovation Center, Zurich, Switzerland., Dumontet C; Univ Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon, France. charles.dumontet@chu-lyon.fr.; Hospices Civils de Lyon, Lyon, France.
المصدر: Molecular cancer therapeutics [Mol Cancer Ther] 2020 Nov; Vol. 19 (11), pp. 2371-2381. Date of Electronic Publication: 2020 Aug 26.
نوع المنشور: Journal Article; Research Support, Non-U.S. Gov't
اللغة: English
بيانات الدورية: Publisher: American Association for Cancer Research, Inc Country of Publication: United States NLM ID: 101132535 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1538-8514 (Electronic) Linking ISSN: 15357163 NLM ISO Abbreviation: Mol Cancer Ther Subsets: MEDLINE
أسماء مطبوعة: Original Publication: Philadelphia, PA : American Association for Cancer Research, Inc., c2001-
مواضيع طبية MeSH: Drug Antagonism*, Antineoplastic Agents, Immunological/*pharmacology , Calcium Channel Blockers/*pharmacology , Early Growth Response Protein 1/*antagonists & inhibitors , Rituximab/*pharmacology, Animals ; Antigens, CD20 ; Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Cell Line, Tumor ; Cell Survival/drug effects ; Disease Models, Animal ; Early Growth Response Protein 1/metabolism ; Humans ; Lymphoma, Large B-Cell, Diffuse/diagnosis ; Lymphoma, Large B-Cell, Diffuse/drug therapy ; Lymphoma, Large B-Cell, Diffuse/mortality ; Mice ; NIH 3T3 Cells ; Prognosis ; Signal Transduction ; Treatment Outcome ; Xenograft Model Antitumor Assays
مستخلص: Direct cell death induction, in addition to immune-effector cell-mediated mechanisms, is one of the key mechanisms of action of anti-CD20 antibodies, and yet the signaling pathways implicated remain poorly investigated. Here we show that the transcription factor EGR-1 is rapidly induced by anti-CD20 antibodies and is a key mediator for CD20-induced cell death. EGR-1 induction results from an increased calcium influx induced by anti-CD20 antibodies. We show that both rituximab and obinutuzumab induce calcium influx, albeit through different mechanisms, and this influx is crucial for cell death induction. Inhibition of the calcium flux with calcium channel blockers (CCB) abolished EGR-1 induction and impaired the efficacy of anti-CD20 antibodies in preclinical in vitro and in vivo models. Finally, we investigated the impact of CCBs in patients treated with anti-CD20 antibodies included in the clinical trials GOYA and REMARC, and found that patients simultaneously receiving CCBs and anti-CD20 therapy have a shorter progression-free survival and overall survival. These results reveal EGR-1 as a key mediator of the direct cytotoxic activity of anti-CD20 antibodies and provide a rationale to evaluate EGR-1 expression as a new biomarker to predict response to anti-CD20 treatment. In addition, our findings show that calcium influx is required for anti-CD20-mediated tumor cell death and suggest that simultaneous administration of calcium channel blocking agents could be deleterious in patients receiving anti-CD20-based immunotherapy.
(©2020 American Association for Cancer Research.)
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المشرفين على المادة: 0 (Antigens, CD20)
0 (Antineoplastic Agents, Immunological)
0 (Calcium Channel Blockers)
0 (EGR1 protein, human)
0 (Early Growth Response Protein 1)
4F4X42SYQ6 (Rituximab)
تواريخ الأحداث: Date Created: 20200828 Date Completed: 20220120 Latest Revision: 20220120
رمز التحديث: 20240628
DOI: 10.1158/1535-7163.MCT-19-0839
PMID: 32847969
قاعدة البيانات: MEDLINE
الوصف
تدمد:1538-8514
DOI:10.1158/1535-7163.MCT-19-0839