Scientists uncover key driver of treatment-resistant cancer

(Press-News.org) University of California San Diego researchers have discovered the enzyme responsible for chromothripsis, a process in which a single chromosome is shattered into pieces and rearranged in a scrambled order, allowing cancer cells to rapidly evolve and become resistant to treatment. Since its discovery more than a decade ago, chromothripsis has emerged as a major driver of cancer progression and treatment resistance, but scientists haven’t learned what causes it. Now, UC San Diego scientists have solved this longstanding mystery in cancer biology, opening up new possibilities for treating the most aggressive cancers. The results are published in Science.

Chromothripsis is just one of several mechanisms cancer cells use to evolve and resist therapy, but it stands out because of its scale. Instead of accumulating mutations gradually, chromothripsis can generate dozens to hundreds of genomic alterations in a single catastrophic event, accelerating cancer evolution dramatically. It is also remarkably common: researchers estimate that approximately one in four human cancers shows evidence of chromothripsis, and for some tumors the rate is even higher. For example, virtually all osteosarcomas — an aggressive bone cancer — display chromothripsis, and many brain cancers show unusually high levels as well.

“This discovery finally reveals the molecular ‘spark’ that ignites one of the most aggressive forms of genome rearrangement in cancer,” said senior author Don Cleveland, Ph.D., professor of cellular and molecular medicine at UC San Diego School of Medicine and member of UC San Diego Moores Cancer Center. “By finding what breaks the chromosome in the first place, we now have a new and actionable point of intervention for slowing cancer evolution.”

Chromothripsis occurs after errors in cell division cause individual chromosomes to become trapped inside tiny, fragile structures called micronuclei. Once a micronucleus bursts, its chromosome is left exposed and vulnerable to nucleases, enzymes that are capable of breaking DNA apart.

Before now, scientists didn’t know which specific nuclease triggers chromothripsis, making it impossible to target the process with cancer treatments.

To answer this question, the researchers used an imaging-based screening technique to comb through all known and predicted human nucleases and observe how they affect human cancer cells in real time. Their analysis found one enzyme, called N4BP2, that is uniquely capable of entering micronuclei and breaking DNA apart.

To prove that N4BP2 actually causes chromothripsis, the researchers then eliminated the enzyme in brain cancer cells. They found that eliminating N4BP2 sharply reduced chromosome shattering, while forcing N4BP2 into the cell nucleus caused intact chromosomes to break, even in otherwise healthy cells.

“These experiments showed us that N4BP2 isn’t just correlated with chromothripsis. It is sufficient to cause it,” said first author Ksenia Krupina, Ph.D., a postdoctoral fellow at UC San Diego. “This is the first direct molecular explanation for how catastrophic chromosome fragmentation begins.”

The researchers also analyzed more than 10,000 human cancer genomes across many cancer types, finding that tumors with high N4BP2 expression showed significantly more chromothripsis and structural rearrangements. These cancers also exhibited elevated levels of extrachromosomal DNA (ecDNA) —circular DNA fragments that carry cancer‑promoting genes and are strongly linked to treatment resistance and aggressive growth.

Because tumors that contain ecDNA tend to be among the most difficult to treat, ecDNA has gained widespread scientific attention in recent years, including being named one of the Cancer Grand Challenges by the National Cancer Institute and Cancer Research UK. The new UC San Diego findings reveal that ecDNA is not an isolated phenomenon, but rather a downstream consequence of the much broader phenomenon of chromothripsis. By placing N4BP2 at the very start of this process, the study identifies a new molecular entry point for understanding — and potentially controlling — the most chaotic forms of genome instability in cancer.

“Understanding what triggers chromothripsis gives us a new way to think about stopping it,” said Cleveland. “By targeting N4BP2 or the pathways it activates, we may be able to limit the genomic chaos that allows tumors to adapt, recur and become drug‑resistant.”

Link to full study: https://doi.org/10.1126/science.ado0977 

Additional coauthors of the study include Alexander Goginashvili, Michael W. Baughn, Stephen Moore, Christopher D. Steele, Amy T. Nguyen, Daniel L. Zhang, Prasad Trivedi, Aarti Malhotra, David Jenkins, Andrew K. Shiau, Yohei Miyake, Tomoyuki Koga, Shunichiro Miki, Frank B. Furnari and Ludmil B. Alexandrov, all at UC San Diego and Jonas Koeppel and Peter J. Campbell of the University of Cambridge and the Wellcome Trust Sanger Institute.

The study was funded, in part, by the National Institutes of Health (grants R35GM122476, R01 ES030993-01A1, R01ES032547-01, U01CA290479-01, R01CA269919-01, R56 NS080939 and R01 CA258248).

Disclosures: Ludmil Alexandrov is cofounder, scientific advisory board member and consultant for io9; has equity; and receives income. His spouse is an employee of Biotheranostics, and he also declares U.S. provisional patent applications serial numbers 63/289,601; 63/269,033; 63/483,237; 63/366,392; 63/412,835; and 63/492,34. Andrew K. Shiau and David Jenkins are employees of FENX Therapeutics.

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