Study famous how ecDNA fragments pressure gene amplification to generate drug resistance in cancer

Overview

• Post By : Kumar Jeetendra


• Source: Ludwig Institute for Cancer Research


• Date: 26 Dec,2020

Researchers headed by Ludwig San Diego Member Don Cleveland and Peter Campbell of the Sanger Center have solved the puzzle of how free-floating circular DNA fragments, which are almost exclusively found in cancer cells, drive gene amplification to create drug resistance in cancer.

The study, published on December 23 in the journal Nature, provides new insights into how cancers evolve to adapt to changing environments and suggests ways to reduce drug resistance by combining therapies.

Extrachromosomal DNAs (ecDNA) are different 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 tumors grow and survive.

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 in the University of California San Diego School of Medicine first reported in 2017 that it’s found in nearly half of all tumor types and that it plays a big 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, initiate the formation of ecDNA.

Chromothripsis was first described in 2011 by a team headed by Campbell. Scientists hypothesized at the time that chromosomal shattering could produce DNA snippets that circularize to form ecDNA, but this hasn’t yet been proven until now.

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

“We have watched these pieces evolve with time as they get shattered and reshattered,” Cleveland said. “That means if an ecDNA fragment acquires a gene that encodes for a product that directly counters an anticancer drug, it can make more and more of it, resulting in drug resistance.

While chromothripsis occurs naturally in cancer cells, the researchers found that it can also be induced by chemotherapeutic drugs such as methotrexate, which kill dividing cells by damaging their DNA. Additionally, the particular kind of DNA damage these medications cause–breaking both strands of the DNA double helix–provides an opening for ecDNA to reintegrate back into chromosomes.

“We show that if we break a chromosome, these ecDNAs have a tendency to jump into the break and seal themserving almost like a’DNA adhesive,'” Shoshani stated. Thus, some of those very drugs used to treat cancers might also be driving drug resistance by generating double-stranded DNA breaks.

The researchers found that such ecDNA formation could be halted by pairing chemotherapeutic drugs with molecules which block 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 decreased the development of drug resistance.

“This means that 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 improve clinical outcomes,” Shoshani stated.

Cleveland added,”I think the area has approved that combination therapy is the way we are going to generate better results for cancer patients, but here is a particular example of what kinds of mixtures should be tested.”