19 septiembre 2016

PM01183 . Lurbinectedin Specifically Triggers the Degradation of Phosphorylated RNA Polymerase II and the Formation of DNA Breaks in Cancer Cells .

Molecular Cancer Therapeutics

Resultado de imagen de pm01183Gema Santamaría Nuñez, Carlos Mario Genes Robles, Christophe Giraudon, Juan Fernando Martínez-Leal, Emmanuel Compe, Frédéric Coin, Pablo Aviles, Carlos María Galmarini and Jean-Marc Egly .

Published 14 September 2016 .

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); 1–14. ©2016 AACR.