Potential Weakness in Cancer Cells Uncovered

January 28, 2021 –

Multiple genetic alterations, ranging from mutations to aneuploidy, drive the development of cancer. Aneuploidy, the presence of an abnormal number of chromosomes in cancer cells, has long been recognized as a hallmark of cancer, yet its understanding remains limited. However, a recent study from Tel Aviv University (TAU) sheds light on aneuploidy’s potential vulnerability, suggesting a breakthrough in the development of drugs that could effectively eliminate cancer cells.

Published in the journal Nature under the title “Aneuploidy renders cancer cells vulnerable to mitotic checkpoint inhibition,” the study was conducted in the laboratory of Uri Ben-David, PhD, an assistant professor at TAU’s Sackler Faculty of Medicine, in collaboration with six laboratories from four other countries.

The researchers proposed, “Selective targeting of aneuploid cells is an attractive strategy for cancer treatment. However, it is unclear whether aneuploidy generates any clinically relevant vulnerabilities in cancer cells. Here we mapped the aneuploidy landscapes of about 1,000 human cancer cell lines, and analyzed genetic and chemical perturbation screens to identify cellular vulnerabilities associated with aneuploidy.”

Aneuploidy, identified as the most common genetic change in cancer by Ben-David, accounts for approximately 90% of solid tumors, including breast and colon cancer, and 75% of blood cancers. Advanced bioinformatics methods were employed to quantify aneuploidy in around 1,000 cancer cell cultures. The researchers then compared the genetic dependency and drug sensitivity of cells with high levels of aneuploidy to those with low levels.

The study uncovered heightened sensitivity in cancer cells with a high level of aneuploidy to damage to the mitotic checkpoint. The researchers also identified the molecular basis for this increased sensitivity in aneuploid cancer cells.

“Aneuploid cancer cells became increasingly sensitive to inhibition of SAC over time,” the researchers noted. “Aneuploid cells exhibited aberrant spindle geometry and dynamics and kept dividing when the SAC was inhibited, resulting in the accumulation of mitotic defects and in unstable and less-fit karyotypes. Therefore, although aneuploid cancer cells could overcome inhibition of SAC more readily than diploid cells, their long-term proliferation was jeopardized.”

While drugs targeting the delay in separating chromosomes are currently undergoing clinical trials, the response of individual patients remains unknown. These findings suggest that aneuploidy could serve as a biological marker, potentially identifying patients who may respond more favorably to these drugs.

“It should be emphasized that the study was done on cells in a culture and not on cancer patients. In order to translate it to the 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,” emphasized Ben-David.