How Cancer Cells Become Resistant To Treatment?

Chromothripsis is a fatal genetic mutation that results in the formation of extra-chromosomal DNA (ecDNA) that promotes drug resistance.

Cancer cell’s growth is promoted by a phenomenon called as chromothripsis that breaks up chromosomes, which then reassembles. Cancer is one of the greatest threats because, unlike other diseases, it is a moving target, constantly evolving to evade and resist treatment.

The research conducted at the University of California San Diego School of Medicine and the UC San Diego branch of the Ludwig Institute for Cancer Research, with colleagues in New York and the United Kingdom is published in the journal Nature.

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‘Chromothripsis is a fatal genetic mutation that results in the formation of extra-chromosomal DNA (ecDNA) that promotes resistance to the therapy.’
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Chromothripsis is a fatal mutational event in the life cycle of a cell that involves massive rearrangement of its genome, instead of a gradual rearrangements and mutations over time. Genomic rearrangement is a key characteristic of many cancers, which allows the mutated cells to grow faster and shows resistance to cancer therapy.

First author of the study Ofer Shoshani, PhD, a postdoctoral fellow in the lab of the paper's co-senior author Don Cleveland, PhD, professor of medicine, neurosciences and cellular and molecular medicine at UC San Diego School of Medicine said, “These rearrangements can occur in a single step. During chromothripsis, a chromosome in a cell is shattered into many pieces, hundreds in some cases, followed by reassembly in a shuffled order. Some pieces get lost while others persist as extra-chromosomal DNA (ecDNA). Some of these ecDNA elements promote cancer cell growth and form minute-sized chromosomes called 'double minutes.”

How Chromothripsis Drives Cancer

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Earlier studies have found that half of all the cancer cells in many types of cancers contain ecDNA carrying cancer-promoting genes.

For the current study, the researchers used a direct technique for the visualization of chromosome structure to identify the steps in gene amplification and the mechanism underlying resistance to methotrexate, which is one of the earliest chemotherapy drugs and still widely used.

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The team sequenced the entire genome of cells developing resistance and showed that the breakdown of chromosomes jump-starts the formation of ecDNA-carrying genes that results in resistance to anti-cancer therapy.

After gene amplification inside a chromosome, the scientists identified how chromothripsis drives ecDNA formation.

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Shoshani said, "Chromothripsis converts intra-chromosomal amplifications (internal) into extra-chromosomal (external) amplifications and that amplified ecDNA can then reintegrate into chromosomal locations in response to DNA damage from chemotherapy or radiotherapy. The new work highlights the role of chromothripsis at all critical stages in the life cycle of amplified DNA in cancer cells, explaining how cancer cells can become more aggressive or drug-resistant."

The identification of repetitive shattering of DNA that acts as a driver of anti-cancer drug resistance and DNA repair pathways necessary for reassembling the shattered chromosomal pieces has enabled the design of combination drug therapies to prevent development of drug resistance in cancer patients, thereby improving their outcome.

Source-Medindia