Targeting Extra Chromosomes in Cancer Cells May Offer New Treatment Approach

A recent study led by researchers at Yale University has revealed that cancer cells with extra chromosomes rely on those chromosomes for tumor growth, and eliminating them prevents the formation of tumors. The findings suggest that selectively targeting extra chromosomes could potentially be a novel route for cancer treatment. The study, published in Science, focused on aneuploidy, an anomaly characterized by an abnormal number of chromosomes.

While normal human cells typically have 23 pairs of chromosomes, aneuploidy is prevalent in nearly all cancers. However, the role of extra chromosomes in cancer development and progression has remained unclear. To gain insights into their function, the researchers utilized CRISPR gene-editing technology to develop a new approach called Restoring Disomy in Aneuploid cells using CRISPR Targeting (ReDACT). This technique allowed them to eliminate entire chromosomes from cancer cells, providing a significant technical advancement in understanding aneuploidy.

The team applied ReDACT to melanoma, gastric cancer, and ovarian cell lines, specifically targeting an aberrant third copy of the long portion of chromosome 1, known as the "q arm." Removing this extra copy compromised the malignant potential of the cells and inhibited their ability to form tumors. This led the researchers to propose the concept of "aneuploidy addiction," akin to the notion of "oncogene addiction," where disrupting specific oncogenes inhibits tumor formation.

Further investigation revealed that multiple genes were overexpressed when encoded on three chromosomes instead of the usual two, promoting cancer cell growth. The researchers identified a vulnerability in cancer cells with aneuploidy by exploiting the overexpression of a gene called UCK2 on chromosome 1. These cells proved to be more sensitive to certain drugs that required UCK2 activation. By exposing aneuploid cells to these drugs, the researchers observed a shift away from aneuploidy and toward cells with normal chromosome numbers, reducing the potential for malignancy.

Although more research is needed before clinical trials can be conducted, the findings provide a potential therapeutic target for cancer treatment. By selectively targeting aneuploid cells, which are present in almost all cancers, it may be possible to achieve cancer-specific treatment while minimizing harm to normal, non-cancerous tissue. The research team plans to advance their work into animal models, explore additional drugs and aneuploidies, and collaborate with pharmaceutical companies to progress toward clinical trials, aiming for clinical translation and the potential development of a new cancer treatment approach.