Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells

Mol Cancer Ther. 2016 Oct;15(10):2399-2412. doi: 10.1158/1535-7163.MCT-16-0172. Epub 2016 Sep 14.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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


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