|*.- Carlos Galmarini, PharmaMar, Madrid, Spain .|
|*.- Jean-Marc Egly, IGBMC, CNRS, INSERM, University of Strasbourg, Strasbourg, France .|
*.- Institute Humanitas, Milan, Italy .
*.- Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy .
Cancer cells are characterized by their relentless need for active transcription, which reaches the level of real addiction in solid tumors such as small cell lung cancer or triple-negative breast cancer.
Pharmacological modulation of transcription may thus provide a therapeutic approach to treat tumor types that depend on deregulated transcription for the maintenance of their oncogenic state.
Lurbinectedin (PM1183) is a new synthetic compound from the tetrahydroisoquinoline family, which has demonstrated strong anti-proliferative activity against a panel of human tumor models in preclinical assays and is currently being evaluated in phase III clinical trials in platinum-resistant ovarian cancer and small-cell lung cancer. In this work we demonstrate that lurbinectedin inhibits the transcription process through (1) its binding to CG rich sequences, mainly located around promoters of protein coding genes; (2) the irreversible stalling of elongating RNA polymerase II (Pol II) on the DNA template and its specific degradation by the ubiquitin/proteasome machinery and (3) 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.
Combined with this intrinsic activity against cancer cells, lurbinectedin also has the ability to modulate active transcription in the inflammatory tumor microenvironment with a specific focus on myeloid cells.
Besides its direct effect on tumor-associated macrophages, lurbinectedin also inhibited the production of inflammatory/trophic mediators (e.g. CCL2, CXCL8 and VEGF) by mononuclear phagocytes. Altogether, our results help to better understand the high specificity of this drug in cancer therapy.
In summary, lurbinectedin exemplifies a prototypical drug for targeting transcriptional dependency in tumor cells and, thus, it could represent a new therapeutic alternative for solid tumors with this addiction.