UC San Diego researchers have identified an enzyme that scrambles cancer genomes, making it harder for treatments to work. This discovery could lead to new treatment options for aggressive cancers. Chromothripsis is a process where a single chromosome is broken into pieces and rearranged in a chaotic order, allowing cancer cells to rapidly evolve and resist therapy.
The researchers used imaging-based screening techniques to find the enzyme responsible for chromothripsis. They discovered that N4BP2, an enzyme capable of breaking DNA apart, triggers this process. Eliminating N4BP2 reduced chromosome shattering in brain cancer cells, while forcing it into the nucleus caused intact chromosomes to break.
The study found that tumors with high N4BP2 expression showed more chromothripsis and structural rearrangements. These cancers also had elevated levels of extrachromosomal DNA (ecDNA), which carries cancer-promoting genes and is linked to treatment resistance. The researchers believe targeting N4BP2 could limit the genomic chaos that allows tumors to adapt, recur, and become drug-resistant.
This breakthrough opens up new possibilities for treating aggressive cancers and could lead to a better understanding of the molecular mechanisms behind chromothripsis.
Source: https://today.ucsd.edu/story/scientists-uncover-key-driver-of-treatment-resistant-cancer