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Whole genome doubling causes multidrug resistance

Oss, July 7th, 2015 – In a new study in Cell Cycle, researchers from the Max Planck Institute and NTRC show that doubling of the whole genome of human cancer cells provides resistance to a broad spectrum of chemotherapeutic drugs. Also non-transformed cells become multidrug resistant upon genome doubling. Importantly, genome doubling also causes chromosomal instability and tolerance to mitotic errors. Overall, the creation of tetraploid (4n) cells from ‘normal’ diploid (2n) cells results in a cellular phenotype that correlates with poor survival in cancer.
The study was carried out in the context of the European Commission-funded ‘PloidyNet’ project in which NTRC, Dr. Zuzana Storchova and her team from the Max Planck Institute of Biochemistry (Martinsried, Germany) and other academic and industrial partners study the consequences of ‘aneuploidy’, an abnormal number of chromosomes in cells. In the article in Cell Cycle, Dr. Storchova and collaborators show that whole genome doubling has far reaching consequences for human cells, leading to aneuploidy and chromosomal instability. This is an important finding, as DNA sequence analysis of cancer genomes indicates that 40 % of tumors undergo genome doubling at some point of tumorigenesis. Parallel compound profiling studies performed at NTRC revealed that the tetraploid cells are resistant to various, but not all cytotoxic agents as well as to a number of targeted therapies. The low level multidrug resistant phenotype may be clinically important, and will be further investigated in the collaboration between NTRC and the team at the Max Planck Institute of Biochemistry.
Reference: Kuznetsova et al. (2015) Chromosomal instability, tolerance of mitotic errors and multidrug resistance are promoted by tetraploidization in human cells. Cell Cycle, published online first 7 July 2015 {DOI:10.1080/15384101.2015.1068482}