State of the art

Our program aims to use synthetic lethality approaches to attack a major inherent weakness of cancers, the presence of DNA replication stress. Synthetic lethality arises when the combination of alterations in two genes or pathways leads to cell death, whereas the alteration in only one of these genes or pathways is viable. Genetic changes such as BRCA1/2 mutation leads to replication stress, which is a major alteration that weakens cancer cells. Our consortium will identify pathways that when inhibited lead to death of cells with replication stress, including BRCA1/2 deficiency.  

The presence of DNA replication stress in the majority of human cancers was first proposed a little more than ten years ago by three members of this consortium; Jiri Bartek, Thanos Halazonetis and Vassilis Gorgoulis. While this finding was initially met with scepticism, it is now widely accepted that DNA replication stress accounts for a significant fraction of the genomic instability observed in human cancers. A little more than ten years ago, breakthrough research uncovered that PARP1 inhibitors exhibit synthetic lethality with BRCA1/2-deficiency (co-discovered by consortium member Thomas Helleday). This synthetic lethality interaction resulted in the approval by the FDA of the PARP-inhibitor Olaparib for the treatment of advanced ovarian cancer in late 2014. 

Unfortunately, our knowledge of the pathways by which cells respond to DNA replication stress is still limited, which impacts our ability to target this inherent cancer weakness. As examples, BRCA1/2 are important for stabilizing stalled DNA replication forks, but the mechanistic basis of this effect is unknown. Break-induced replication (BIR) as a major repair pathway for replication stress-induced fork collapse in cancer cells was only described two years ago (by Thanos Halazonetis), but how BIR functions at the molecular level is still largely unknown. In fact, the gaps in knowledge regarding DNA replication in human cells are so large that even the genomic positions of most DNA replication origins are not known. Our Consortium is at the forefront of this research field. Working together, we are poised to identify and elucidate the molecular pathways by which cells respond to replication stress, the role of BRCA1/2 in this response and how the various repair pathways work together to maintain genomic stability in the presence of replication stress. This knowledge will be exploited by identifying synthetic lethality interactions, on which cancer-specific therapeutic targets and lead chemical compounds will be identified.

This field will move rapidly in the next ten years, and the ESRs that will be trained in this field will have the knowledge and skills needed to make important contributions to our society.