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: Gema Santamaría Nuñez, Carlos Mario Genes Robles, Christophe Giraudon, Juan Fernando Martínez-Leal, Emmanuel Compe, Frédéric Coin, Pablo Aviles, Carlos María Galmarini, Jean-Marc Egly
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 15 Issue 10 Pg. 2399-2412 (10 2016) ISSN: 1538-8514 [Electronic] United States
• PMID: 27630271 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2016 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Biological Products
• Ubiquitin
• RNA Polymerase II
• Proteasome Endopeptidase Complex

Topics

• Animals
• Antineoplastic Agents (chemistry, pharmacology)
• Aquatic Organisms (chemistry)
• Biological Products (chemistry, pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA Breaks
• Disease Models, Animal
• Female
• Humans
• Mice
• Neoplasms (drug therapy, genetics, metabolism, pathology)
• Phosphorylation
• Proteasome Endopeptidase Complex (metabolism)
• Protein Binding
• Proteolysis
• RNA Polymerase II (metabolism)
• Transcription, Genetic
• Transcriptional Activation
• Ubiquitin (metabolism)
• Xenograft Model Antitumor Assays