Ludwig Cancer Research study reveals how ecDNA creates and manages cancer drug resistance

DECEMBER 23, 2020, NEW YORK – Researchers led by San Diego Ludwig Ball Don Cleveland and Peter Campbell of the Sanger Center have uncovered the mystery of how floating free DNA fragments which is virtually present in cancer cells, directing gene proliferation to generate drug resistance in cancer. The research, published on December 23, is published in the journal Nature, offers new insights into how cancers evolve to adapt to changing environments and suggests ways to reduce drug resistance by combining treatments.

“Drug resistance is the most difficult part of cancer treatment,” said Ofer Shoshani, a postdoctoral researcher at the Cleveland lab and the first author in the study. “If it weren’t for the fight against drugs, a lot of cancer patients would be alive.”

Extrachromosomal DNA (ecDNA) are specific circular units of non-chromosome DNA, which pack genomic DNA into the nucleus of the cell. ecDNA can contain many copies of cancer genes that help tumors grow and survive. Understanding the biology and origins of ecDNA took a turn for the worse after a team led by San Diego Ludwig Member Paul Mischel and his colleague Vineet Bafna at the University of California San Diego School of Medicine first reported in 2017 that found in nearly half of all tumor types and plays a major role in the growth and diversity of cancer cells.

In the new study, Shoshani, Cleveland, Campbell and colleagues show that chromothripsis, chromosome breakdown and their recombination in a mobile order, initiate ecDNA formation.

Chromothripsis was first reported in 2011 by a team led by Campbell. Scientists were speculating at the time that chromosomal breakdown could produce circulating DNA fragments to form ecDNA, but this has not been proven to date. “What we were able to show was the link between chromosomal disruption and ecDNA formation,” Cleveland said. The team also showed that ecDNA itself can undergo continuous cycles of chromothripsis to spawn reorganized ecDNAs that provide even higher drug protection.

“We’ve seen these pieces grow over time as they break down and regenerate,” Cleveland said. “That means if an ecDNA fragment gets a gene encoding for a result that is directly against anticancer drug, it can make it more and more, leading to drug resistance. We have now established this in three different cell lines forming methotrexate resistance and in biopsies from human colorectal cancer patients versus BRAF therapy. ”

While chromothripsis occurs naturally in cancer cells, the researchers found that it can also be stimulated by chemotherapeutic drugs such as methotrexate, which kill cell division by damaging the They have DNA. In addition, the specific type of DNA damage caused by these drugs – breaking both layers of the DNA double helix – allows ecDNA to re-enter into chromosomes.

“We show that when we break a chromosome, these ecDNAs tend to jump into the fracture and seal, serving almost as a‘ DNA call, ’” Shoshani said. Thus, some of the real drugs used to treat cancer could lead to drug resistance by generating two-stranded DNA fragmentation.

The researchers found that such ecDNA formation can be prevented by fixing chemotherapeutic drugs with molecules that prevent the DNA fragments generated by chromosomal breakdown from closing into form circles. Shoshani showed that, when applied in combination with cancer cells, this strategy inhibited the formation of ecDNA and reduced drug resistance.

“This means that an approach in which we combine DNA repair inhibitors with drugs such as methotrexate or vemurafenib could prevent drug resistance in cancer patients and improve clinical outcomes,” Shoshani said.

Cleveland said, “I think the field has accepted that combination therapy is how we are going to generate better outcomes for cancer patients, but this is a specific example of the types of combinations that should be used. confirmation. “

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This study was supported by Ludwig Cancer Research, the U.S. National Institutes of Health and the Wellcome Trust.

In addition to his Ludwig position, Don Cleveland is chair of the Department of Cellular and Molecular Medicine and is a professor of Medicine, Neurosciences and Cellular and Molecular Medicine at UC San Diego.

About Ludwig’s Cancer Research

Ludwig Cancer Research is an international collaborative network of renowned scientists who have studied and discovered cancer for nearly 50 years. Ludwig combines basic science with the ability to translate its findings and conduct clinical trials to accelerate the development of new cancer diagnoses and treatments. Since 1971, Ludwig has invested $ 2.7 billion in life-changing science through the nonprofit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http: // www.ludwigcancerresearch.org.

For more information contact Rachel Reinhardt, [email protected].