Researchers from UT Southwestern Medical Centre conducted a landmark study that revealed how cancer cells hijack a crucial genetic process involved in DNA repair to fuel malignancy and build resistance to cancer treatments. The discoveries, published in the journal Cell, provide fresh insights into how chromosomes in tumours acquire significant rearrangements and indicate prospective ways for combating cancer medication resistance.

Dr. Peter Ly, Ph.D., Assistant Professor of Pathology and Cell Biology, leading the research team, identified chromothripsis, or the shattering and reassembling of chromosomes, as a crucial role in the evolution of cancer genomes. This process causes significant chromosome rearrangements, which can promote malignancy and allow cancer cells to rapidly acquire genetic alterations.

Dr. Ly added, "Our findings address a critical mechanistic concern in cancer biology by identifying a source of chromothripsis, a mutational process caused by chromosome shattering. Chromothripsis enables cancer cells to rapidly change their genomes by extensively rearranging individual chromosomes, resulting in numerous genetic mutations in a short amount of time."

Chromothripsis affects 30-40% of all cancers, and it is especially prevalent in aggressive forms such as sarcomas, glioblastomas, and pancreatic cancer. This research sheds light on how these malignancies develop resistance to medicines and continue to progress despite treatment efforts.

The study found that malfunctions in mitosis, the normal process of cell division, frequently cause chromothripsis. During this process, entire chromosomes or substantial parts of chromosomes may wind up outside the nucleus in small, aberrant formations known as micronuclei. Unlike chromosomes in the nucleus, those in micronuclei fail to replicate properly, resulting in genomic instability.

Dr. Ly's team employed CRISPR, a potent gene editing technology, to disable several genes involved in this process. Their findings focused on the Fanconi anaemia pathway, a DNA repair mechanism named after a rare genetic illness. Researchers discovered that the Fanconi anaemia pathway plays a critical role in chromosomal shattering. When the researchers activated this process in cells, the chromosomes did not fragment as much.

Dr. Ly explains, "When the Fanconi anaemia pathway activates, an enzyme complex chops these chromosomes into pieces, causing the shattering characteristic of chromothripsis." Frequently, incorrect sewing stitches the resultant fragments back together, leading to chromosomal rearrangements. These changes could turn off important genes that fight cancer or create extrachromosomal DNA (ecDNA), a ring-shaped structure of DNA that can help oncogenes grow and make it harder for medicines to work.

To investigate the therapeutic implications of these findings, the researchers inhibited the Fanconi anaemia pathway in melanoma cells treated with targeted treatments. Normally, these cancer cells would become drug-resistant over time. However, the study discovered that cells lacking the Fanconi anaemia pathway could not undergo chromothripsis and were therefore unable to acquire resistance to the treatment.

This research suggests a possible new option for cancer treatment. Dr. Ly said: "These findings could eventually lead to new strategies incorporating Fanconi anaemia pathway inhibition with other drugs to combat the emergence of therapy-resistant cancer cells, which represents a significant problem for cancer patients."

Researchers believe that by addressing the Fanconi anaemia pathway, they may be able to avoid the chromosomal shattering that causes drug resistance, paving the way for more effective cancer therapy.

The study's findings pave the way for the development of medications that target the Fanconi anaemia pathway in combination with existing cancer treatments. This dual approach has the potential to block cancer cells' rapid genetic evolution, making them less likely to develop resistance.

Additional research will be required to establish how best to incorporate these findings into clinical practice, but the ramifications are far-reaching. This method, if effective, could extend to a wide range of tumours with chromothripsis, particularly those notoriously difficult to treat due to drug resistance.