Scientists unveil mystery in the back of drug resistance in cancer through ecDNA forms – science


Researchers from Sanger Center here claimed that the free-floating circular DNA fragments, found in cancer cells, generate drug resistance in cancer.

Published in the publication Nature, a study provides new insights into how cancers evolve to adapt to changing environments and suggests ways to minimize drug resistance by combining therapies.

“Drug resistance is the most problematic a part of cancer therapy. Whether not for drug resistance, many cancer patients would live to tell the tale,” said Ofer Shoshani, a postdoctoral researcher in Cleveland’s lab and the study’s first creator.

Extrachromosomal DNAs (ecDNA) are distinct circular units of DNA that are unassociated with chromosomes, which package genomic DNA in the cell’s nucleus. ecDNA can contain many copies of cancer genes that help tumours grow and live to tell the tale.

Understanding the biology and origins of ecDNA took on some urgency after a team led by Ludwig San Diego Member Paul Mischel and his colleague Vineet Bafna at the University of California San Diego School of Medicine first reported in 2017 that it is found in almost half of all tumour types and that it plays a major role in the growth and diversity of cancer cells.

In the new study, Shoshani, Cleveland, Campbell and colleagues show that chromothripsis, the shattering of chromosomes and their reassembly in shuffled order, initiates the formation of ecDNA.

Chromothripsis used to be first described in 2011 by a team led by Campbell. Scientists hypothesized at the time that chromosomal shattering could produce DNA snippets that circularize to form ecDNA, but this has not been proven until now.

“What we were ready to show is the link between chromosomal shattering and the formation of ecDNA,” Cleveland said. The team also showed that ecDNA can itself undergo successive rounds of chromothripsis to spawn rearranged ecDNAs that supply even higher drug resistance.

“We’ve watched these pieces evolve with time as they get shattered and reshattered. That means whether an ecDNA fragment acquires a gene that encodes for a product that directly counters an anticancer drug, it can make increasingly of it, leading to drug resistance,” Cleveland said.

“We have now established this in three different cell lines forming a resistance to methotrexate and in biopsies from human colorectal cancer patients forming a resistance to BRAF therapy,” added Cleveland.

While chromothripsis occurs naturally in cancer cells, the researchers found that it may also be induced by chemotherapeutic drugs such as methotrexate, which kill dividing cells by damaging their DNA.

In addition, the specific more or less DNA damage these drugs cause–breaking both strands of the DNA double helix–provides an opening for ecDNA to reintegrate back into chromosomes.”We show that when we break a chromosome, these ecDNAs tend to hop into the break and seal them, serving nearly like a ‘DNA glue,’“ Shoshani said.

Thus, one of the vital very drugs used to treat cancers may additionally be driving drug resistance by generating double-stranded DNA breaks.The researchers found that such ecDNA formation will also be halted by pairing chemotherapeutic drugs with molecules that prevent the DNA fragments created by chromosomal shattering from closing to form circles.

Shoshani showed that when applied together to cancer cells, this strategy inhibited the formation of ecDNA and reduced the emergence of drug resistance.

“Which means an approach in which we combine DNA repair inhibitors with drugs such as methotrexate or vemurafenib could potentially prevent the initiation of drug resistance in cancer patients and beef up clinical outcomes,” Shoshani said.

“I think the field has accepted that combination therapy is how we’re going to generate better outcomes for cancer patients, but here’s a particular example of what kinds of combinations will have to be tested,” Cleveland added.

(This story has been published from a wire agency feed without modifications to the text.)

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