The study shows how ecDNA forms and promotes resistance to cancer drugs

The study, published in the journal Nature, offers new insights into how cancers evolve to adapt to changing environments and suggests ways to reduce drug resistance through combinations of therapies.
“Drug resistance is the most problematic part of cancer therapy. Without drug resistance, many cancer patients would survive,” said Ofer Shoshani, a postdoctoral fellow in Cleveland’s laboratory and lead author of the study.
Extrachromosomal DNAs (ecDNA) are different circular DNA units that are not associated with chromosomes and that package genomic DNA in the cell nucleus. ecDNA can contain many copies of cancer genes that promote tumor growth and survival.
Understanding the biology and origins of ecDNA became urgent after a team led by Ludwig San Diego member Paul Mischel and colleague Vineet Bafna of the Medical School of the University of California at San Diego first reported that it was in almost Tumor types occur in half of all cases and that it plays an important role in the growth and diversity of cancer cells.
In the new study, Shoshani, Cleveland, Campbell, and colleagues show that chromothripsis, the breaking up of chromosomes and assembling them in a mixed order, initiates ecDNA formation.
Chromothripsis was first described in 2011 by a team led by Campbell. At the time, scientists hypothesized that chromosome destruction could produce bits of DNA that circulate to form ecDNA. However, this has not yet been proven.
“What we were able to show is the link between chromosome destruction and the formation of ecDNA,” said Cleveland. The team also showed that ecDNA can itself go through successive rounds of chromothripsis to yield rearranged ecDNAs that offer even higher drug resistance.
“We have observed how these parts evolve over time as they are broken and shattered again. That is, if an ecDNA fragment acquires a gene that codes for a product that directly counteracts a cancer drug, it can do more make resistance out of it and lead to drugs, “Cleveland said.
“We have now seen this in three different cell lines that are resistant to methotrexate and in biopsies from human colon cancer patients that are resistant to BRAF therapy,” added Cleveland.
While chromothripsis occurs naturally in cancer cells, the researchers found that it can also be induced by chemotherapy drugs like methotrexate, which kill dividing cells by damaging their DNA.
In addition, the particular type of DNA damage these drugs cause – breaking both strands of the DNA double helix – provides an opening for ecDNA to reintegrate into chromosomes.
“We show that when a chromosome breaks, these ecDNAs tend to jump into the break and seal it, which acts almost like a ‘DNA glue’,” Shoshani said.
Therefore, some of the drugs used to treat cancer could also increase drug resistance by creating double-stranded DNA breaks.
The researchers found that such ecDNA formation can be stopped by pairing chemotherapy drugs with molecules that prevent the DNA fragments created by chromosome breakdown from closing and forming circles.
Shoshani showed that this strategy, when used together on cancer cells, inhibits ecDNA formation and reduces the incidence of drug resistance.
“This means that an approach where we combine DNA repair inhibitors with drugs like methotrexate or vemurafenib can potentially prevent drug-resistance in cancer patients and improve clinical outcomes,” Shoshani said.
“I think the field has accepted that combination therapy can produce better outcomes for cancer patients, but here is a specific example of what types of combinations should be tested,” Cleveland added. (ANI)