A new study from Tel Aviv University has shown, for the first time, how aneuploidy could become a weak point for cancer cells.
Aneuploidy refers to copy number changes that encompass entire chromosome arms or whole chromosomes. It is the most prevalent genetic aberration in human cancer. Approximately 90% of solid tumours and 75% of blood cancers are aneuploid in nature. As cancer cells are mostly aneuploid and normal cells are almost always euploid, researchers have longed to identify aneuploidy-targeting drugs. Whilst researchers have described aneuploidy-augmented cellular vulnerabilities within in yeast, they have not yet been systemically identified in human cancer.
In this study, published in Nature, researchers evaluated the aneuploidy landscapes of 997 human cancer cell lines. They also analysed genetic and chemical perturbation screens to identify cellular vulnerabilities associated with aneuploidy.
The team found that aneuploid cancer cells demonstrated heightened sensitivity to key components of the spindle assembly checkpoint (SAC). This checkpoint ensures that proper separation of chromosomes occurs during mitosis. They also identified a specific kinesin, KIF18A, whose activity was perturbed in aneuploid cancer cells. Aneuploid cancer cells were found to be particularly vulnerable to depletion of KIF18A, and KIF18A overexpression restored their response to SAC inhibition.
These results demonstrate a therapeutically relevant, synthetic lethal interaction between aneuploidy and the SAC. This study also has important implications for the drug discovery process within personalised cancer medicine. These results suggest that aneuploidy could be used as a biological biomarker to identify patients who may respond better to drugs that delay the separation of chromosomes.
Dr. Uri Ben-David of TAU’s Sackler Faculty of Medicine stated:
“It should be emphasised that the study was done on cells in a culture and not on cancer patients. In order to translate it to treatment of cancer patients, many more follow-up studies must be performed. Still, even at this stage it is clear that the study could have a number of medical implications.”
Image credit: By selvanegra – canva.com