Aneuploidy and DNA damage response: an intricate relationship of therapeutic relevance

Aneuploidy, an abnormal number of chromosomes or chromosome-arms, is a hallmark of cancer. Aneuploidy is the outcome of chromosome mis-segregation, and it can also promote further chromosomal and genomic instability. Aneuploidy is associated with increased levels of DNA double-strand breaks, replication stress, and additional copy number alterations. In this talk, I will discuss our recent studies on the multiple bi-directional associations between aneuploidy and the DNA damage response (DDR).

Using a novel system of matched diploid/aneuploid cells, we found aneuploid cells to be more genomically unstable, to upregulate the DDR, and to be less sensitive to DNA damage induction in comparison to their diploid counterparts. Our findings uncover the pathways triggered in response to DNA damage in aneuploid cells, and highlight the importance of RAF/MEK/ERK pathway activation, and CRAF in particular, for the aneuploid DDR. Our data points at a kinase-dependent DDR regulation of RAF/MEK/ERK pathway in aneuploid cells, enabling aneuploid cells to tolerate DNA damage and to keep proliferating in its presence. We validated these findings in additional isogenic systems of aneuploidy, and through a comprehensive analysis of human cancer cell lines. These findings suggest the exciting possibility to combine clinically-approved RAF/MEK/ERK inhibitors with DNA damage-inducing chemotherapies for the targeting of aneuploid tumors.