title: Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells.
abstract: We have defined the mechanism of action of lurbinectedin, a marine-derived drug exhibiting a potent antitumor activity across several cancer cell lines and tumor xenografts. This drug, currently undergoing clinical evaluation in ovarian, breast, and small cell lung cancer patients, inhibits the transcription process through (i) its binding to CG-rich sequences, mainly located around promoters of protein-coding genes; (ii) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery; and (iii) the generation of DNA breaks and subsequent apoptosis. The finding that inhibition of Pol II phosphorylation prevents its degradation and the formation of DNA breaks after drug treatment underscores the connection between transcription elongation and DNA repair. Our results not only help to better understand the high specificity of this drug in cancer therapy but also improve our understanding of an important transcription regulation mechanism. Mol Cancer Ther; 15(10); 2399-412. ©2016 AACR.
authors.affiliation: Cell Biology and Pharmacogenomics Department, Pharmamar SA, Colmenar Viejo, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Santamaría Nuñez
authors.affiliation: Department of Functional Genomics and Cancer, IGBMC, CNRS/INSERM/University of Strasbourg, C. U. Strasbourg, France.
authors.forename: Carlos Mario Genes
authors.initials: CM
authors.lastname: Robles
authors.affiliation: Department of Functional Genomics and Cancer, IGBMC, CNRS/INSERM/University of Strasbourg, C. U. Strasbourg, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Giraudon
authors.affiliation: Cell Biology and Pharmacogenomics Department, Pharmamar SA, Colmenar Viejo, Madrid, Spain.
authors.forename: Juan Fernando
authors.initials: JF
authors.lastname: Martínez-Leal
authors.affiliation: Department of Functional Genomics and Cancer, IGBMC, CNRS/INSERM/University of Strasbourg, C. U. Strasbourg, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Compe
authors.affiliation: Department of Functional Genomics and Cancer, IGBMC, CNRS/INSERM/University of Strasbourg, C. U. Strasbourg, France.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Coin
authors.affiliation: Cell Biology and Pharmacogenomics Department, Pharmamar SA, Colmenar Viejo, Madrid, Spain.
authors.forename: Pablo
authors.initials: P
authors.lastname: Aviles
authors.affiliation: Cell Biology and Pharmacogenomics Department, Pharmamar SA, Colmenar Viejo, Madrid, Spain. cgalmarini@pharmamar.com.
authors.forename: Carlos María
authors.initials: CM
authors.lastname: Galmarini
authors.affiliation: Department of Functional Genomics and Cancer, IGBMC, CNRS/INSERM/University of Strasbourg, C. U. Strasbourg, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Egly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D059001:Aquatic Organisms / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D053960:DNA Breaks; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D059748:Proteolysis; D012319:RNA Polymerase II / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D025801:Ubiquitin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001688:Biological Products; D025801:Ubiquitin; D012319:RNA Polymerase II; D046988:Proteasome Endopeptidase Complex