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Group Leader Angel R. Nebreda and PhD student Begoña Cánovas at the Signalling and Cell Cycle Laboratory (M. Minocri, IRB Barcelona).

Tumour cells evade death through in extremis DNA repair

A study conducted at IRB Barcelona in Barcelona Science Park, published today in the journal Cancer Cell, rreveals a new protective mechanism for tumour cells in breast cancer and identifies novel therapeutic targets to treat this condition. The paper identifies the key role of p38 in safeguarding tumour cells against the excessive accumulation of DNA damage. The results show that p38 blockage ncreases the death of tumour cells, thus causing tumours to shrink.


The results of this study– headed by Angel R. Nebreda, ICREA researcher at IRB Barcelona– demonstrate that the p38alpha (p38 from now on) protein protects tumour cells by turning on a DNA repair mechanism. In this regard, p38 safeguards tumour cells against the excessive accumulation of DNA errors, or mutations. “Tumour cells inherently tend to accumulate DNA damage but in some this accumulation is greater, and we have observed that these cells are more dependent on p38 activity,”explains Nebreda.

Breast cancer is the most lethal tumour in women, causing 521,000 deaths worldwide each year, 6,213 of these in Spain (sources: World Health Organization (2012) and SEOM (2017)). Breast cancer can be classified into three types: estrogen receptor-positive (ER), HER 2-positive or triple negative. The experiments were performed in a mouse model characterised by the development of triple negative breast tumours. This kind of tumour accounts for 15 % of breast cancer cases, and the only treatment to date consists of generic chemotherapy. In contrast, targeted treatments are available for the two other types. These discoveries could pave the way to improving treatment options for triple negative breast tumours.

Blocking p38 to optimise chemotherapy

The researchers used p38 inhibitors to block the action of this protein in tumour cells. These inhibitors have already been used in clinical assays involving patients, but for other diseases. In this study, p38 inhibitors were combined with classical chemotherapeutic drugs called taxanes, such as paclitaxel and docetaxel. As expected, the cells treated with combined therapy showed greater accumulation of genomic instability, that is to say, they carried more DNA damage and a greater number of chromosome variations. Consequently, many of these cells died and the tumour mass shrank considerably.

The scientists used nine tumours from patients, which were grown in mice. In seven of these tumours, including ER and triple negative, the p38 inhibitor strengthened, accelerated or prolonged the antitumour effect of the taxanes.

“Taxanes prevent cell division by damaging chromosomes and causing chromosome instability. As suspected, given that p38 hinders this action, if we switch off the function of this protein in cells, they lose their protection and taxanes can be more effective,” explains Begoña Cánovas, “la Caixa” PhD student and first author or the study together with Ana Igea, postdoctoral fellow and current IRB Barcelona Alumnus at the University of Vigo.

The study has been funded by competitive Advanced and Proof of Concept grants from the European Research Council (ERC).

►More information: IRB Barcelona website [+]